Candiolo Cancer Institute
Fondazione del Piemonte per l’Oncologia
Istituto di Ricovero e Cura a Carattere Scientifico
Scientific Report 2013
www.ircc.it
Candiolo Cancer Institute
Contents
About Us 5
The Link with the University of Torino
7
Mission 9
Research Synopsis11
Mechanisms of Cancer Onset and Progression13
From Molecular Biology to “Precision Medicine”23
Investigational Clinical Oncology
Applied Clinical Research
35
39
Clinical Services55
Grant Office and Research Administration
57
Core Facilities58
List of Publications61
|3
Paolo M.Comoglio MD, Scientific Director - James Dewey Watson, Nobel laureate (lecturing at the institute) - Allegra Agnelli, President of the
Fondazione Piemontese per la Ricerca sul Cancro - Giampiero Gabotto, Managing Director of Fondazione del Piemonte per l’Oncologia
4 | About Us
THE CANDIOLO CANCER INSTITUTE
Candiolo Cancer Institute is a private non-profit institution founded and supported by the Fondazione Piemontese per la
Ricerca sul Cancro-Onlus (FPRC) and operated by the Fondazione del Piemonte per l’Oncologia (FPO: a joint venture
between the FPRC and the Regione Piemonte). It is linked to the University of Torino Medical School. Its mission is a
significant contribution to fight cancer, by understanding the basics, and by providing state-of-the-art diagnostic and
therapeutic services. At the core of the Institute is the interface between molecular biology and medicine. The FPRC
provides enduring fund raising to complete and develop the Institute’s buildings and technologies to foster research.
CANDIOLO CANCER INSTITUTE
About Us | 5
6 | The Link with the University of Torino
THE LINK WITH THE UNIVERSITY OF TORINO
Since its founding, The Candiolo Cancer Institute has been linked to the University of Torino by formal agreements,
the first one contracted in 1994, two years before the completion of the buildings. The cooperation between the Institute and the University was renewed and implemented by a series of agreements signed in the 2002 and in the
2011, to share scientific programs of advanced oncological research. To date, in the Institute operates a branch of the
Department of Oncology, born in 2012, and host a number of investigators scattered among other department of the
University or the Politecnico of Turin. The University Department of Oncology gathers academic competences in the
field of Cancer research, both basic and clinical. The Department belongs to the School of Medicine and its personnel
has teaching responsibilities in academic courses. Students and graduates (PhD and MD) are offered specialized and
meticulous formative programs, in a multidisciplinary environment in house, at pre- and post-doctoral level, aimed at
the underpinning of creative, independent and productive researchers in the cancer field. Embedded in the Candiolo
Cancer Institute, the University of Torino has 19 full or associate professors, 8 technicians, 3 clerks and 66 young researchers, working full-time.
The Link with the University of Torino | 7
8 | Mission
MISSION
Candiolo Cancer Institute is a biomedical and clinical research center entirely devoted to the study and the
treatment of cancer. Its mission is to transfer experimental preclinical information into clinical practice, through
the continuous flow of knowledge from the fields of genetics, molecular and cell biology, pathology.
The Institute aims to offer a significant contribution to the defeat of the disease through scientific research
and clinical practice of excellence. In order to fulfill these goals, the Institute: (i) capitalizes on knowledge by
conducting scientific research in oncology and – at the same time – promoting a fast transfer of knowledge to
the clinical practice; (ii) provides assistance in cancer prevention, including the identification of genetic risk
factors; (iii) performs diagnostic studies, using state-of-the-art instrumentation and technology; (iv) provides a
full cycle of treatment on the premises, employing -besides the best conventional therapies– protocols for novel
targeted therapies and clinical trials for ‘precision medicine’.
Focus
Basic and clinical research makes the Institute of Candiolo a center of excellence focussed in the study,
prevention and treatment of the dreadful complication of cancer, metastasis.
Basic Research
The current knowledge about the mechanisms of cancer onset and progression is provided by basic disciplines,
such as genetics, cell and developmental biology. Thanks to these studies, it is possible to classify tumors not
only on the basis of their site of origin and histopathological features, but , notably, by the identification of the
genetic lesion(s) that support their growth. The tasks of the Institute basic research are aimed at understanding
the mechanisms that control normal cell functions responsible for proliferation, and at analyzing how these
mechanisms are corrupted during neoplastic transformation. The topics include signal transduction, DNA
duplication, cell division, differentiation, senescence, apoptosis and cell motility. Recent studies suggest that
anti-neoplastic therapy is really effective not only when it hits the appropriate molecular target (vide infra), but
especially when hits the cells feeding the tumor mass. Indeed, most of the cells of the neoplastic mass are
quite innocuous and can be attacked with classic therapies, while only a small fraction of them are resistant to
treatment and able to regenerate the tumor. This small subpopulation includes the “cancer stem cells” – strictly
related to normal “stem cells” – which control the development of our organism during embryonic life and allow
us to renew the worn parts in adult life. The up-to-date conceptualization of Cancer defines it as a “somatic,
genetic disease of the stem cells”.
Translational Research (ECMO: Experimental Clinical Molecular Oncology)
Translational research is the “heart” of the Institute, bridging the gap between basic and clinical research. Based
on recent technological advances, genomic analysis makes possible –in a significant percentage of cases– the
identification of genetic alteration(s) with a “driver” role in tumor development. However, the contribution of
each lesion to the transformed phenotype remains elusive. Moreover, knowledge is still insufficient about the
mechanisms that control the lack of response to targeted therapies, even in the presence of the molecular
target (primary resistance), as well as on the mechanisms that lead to progressive attenuation of the response
after prolonged treatment (acquired resistance).
Mission| 9
ECMO research aims at the fulfillment of some ambitious Goals to integrate the traditional prognostic and
diagnostic factors with a detailed characterization of the genetic and functional alterations of the tumor;
to identify new malfunctioning regulatory pathways in cancer; to isolate and study the cancer stem cells; to
develop new preclinical platforms that can reliably disclose –and understand in detail– the prospective results
of clinical practice. The generation of this kind of knowledge is necessary to designt clinical trials that will be
no longer based on empirical observations but on a strong rational.
Investigational Clinical Oncology (INCO)
Cancer is a complex disease, tied to genetic lesions, that increase in number over time, as a consequence of
genetic instability and exposure to environmental carcinogens. Thus, a cell clone proliferates and invades
the adjacent tissues in uncontrolled way. Since cancer cells contain several genetic anomalies, and tend to
accumulate more anomalies as time passes, cancer is a heterogeneous and hard-to-attack disease, just because
it would be necessary to aim at many targets that continuously change. The molecular lesions that cause and
sustain the most tumors are, however, finite in number (the bona fide oncogenes). These findings drove clinical
pharmacology to commit to an epochal effort to create drugs, called “targeted”, able to contrast the function
of specific oncogenes. The strategy of the Institute at Candiolo intends to make significant contributions
to the field of cancer targeted therapy by: (i) identifying pathologies and recruiting patients sensitive to the
therapies currently in use; (ii) planning and performing –in international networks – the related clinical trials;
(iii) developing translational and preclinical research aimed at designing new targeted therapies, if not available
yet.
Molecular diagnosis and “personalized” medicine
The success of targeted therapies is based on the rationale that the target molecule is ‘druggable’ –as a
consequence of the genetic anomaly– in the tumor but not in the healthy tissue, and therefore its deactivation
has consequences restricted to the neoplastic mass, with a minimum of ‘off-target’ consequences, leading to
generic organ damage. This notion has two important clinical outcomes: first of all, before treating patients with
a given targeted therapy, it is necessary to verify the presence of the genetic lesion “predictive” of the sensitivity
to the drug. Second –in the perspective of targeted therapies– the tumors will be classified not only according
to their site of origin and/or morphological features, but also on the molecular lesion(s) which earmarks them
and, at the same time, makes them vulnerable to a targeted treatment. Therefore, new therapies are not only
“targeted” but also “personalized”. This new approach is called “precision medicine”.
Clinical Research
At the Institute, oncologists, surgeons and radiotherapists cooperate with scientists to design clinical trials based
on molecular data, intended to verify hypotheses and generate novel ones. In order to make this cooperation
productive, the Institute manages a daily net of interactions involving formal aspects (seminars and meetings),
training (refresher courses and lessons), operational efforts (contacts with the pharmaceutical companies, and
management of regulatory instruments). Clinical Research is the last and more direct haven to improve the
assistance to cancer patients, providing them with the most appropriate, novel, safe and effective therapeutic
approach, according to the genetic characteristic of their own tumor , as an ultimate means to increase their
life expectancy.
Paolo M.Comoglio MD
(Scientific Director)
10 | Mission
RESEARCH SYNOPSIS
Topic 1: The mechanisms of onset and progression of cancer
1.1 Role of Semaphorins in invasion, metastasis and angiogenesis
1.2 The plasma membrane in cell migration and invasiveness
1.3 Tumor angiogenesis
Topic 2: From Molecular Biology to ‘Precision Medicine’
2.1 Oncogenes and growth factors
2.2 Genetics of the response to anti-cancer therapy
2.3 Preclinical models of ‘personalized’ therapies
2.4 Resistance to targeted therapy
Topic 3: Investigative clinical research: rationale for the planning of clinical trias
3.1 HERACLES e ARES: ‘Precision medicine’ trials for metastatic colon carcinoma
3.2 HERLAP: ‘Personalized’ treatment of mammary carcinoma
3.3 AGNOSTOS: Therapy of metastatic cancers from unknown primary origin
Topic 4: Applied clinical research
4.1 Pathology of colorectal cancer onset and progression
4.2 Implementation of current therapeutic strategies
4.3 Novel approaches to surgical oncology
4.4 Radiotherapy, imaging and laboratory medicine
Research Synopsis | 11
Research Topic 1:
Mechanisms of cancer onset and progression.
The current knowledge on mechanisms of cancer onset and progression has been provided by basic disciplines,
such as cell biology, developmental biology and genetics. The tasks of Research Topic 1 are aimed at
understanding the mechanisms controlling the normal cell functions responsible for the regulation of cell
proliferation and at analyzing how these mechanisms are corrupted during neoplastic transformation. The
topics include signal transduction, DNA duplication and cell division processes, differentiation, senescence,
apoptosis and cell invasion. Special attention is given to the microenvironment and to the relations of the
neoplastic cell with the adjacent cells. In the past, the angiogenic process and the vascularization of the tumor
mass have been studied in detail.
Research Topic 1 is focussed on:
1.1
The role of Semaphorines in invasiveness, metastases and angiogenesis
1.2
The plasma membrane in metastases dissemination
1.3
Tumor angiogenesis
MET gene amplification and MET Protein overexpression in a Human gastric carcinoma
The mechanisms of cancer onset and progression | 13
Semaphorins: structure & functions
Luca Tamagnone MD
Laboratory of Cancer Cell Biology
[email protected]
Rationale
Study of the molecular mechanisms that regulate tumor invasion and
metastatic dissemination, with focus on the signals mediated by Semaphorins,
acting in tumor cells and in cells of the tumor microenvironment.
Results
In preclinical murine models, semaphorin 3E/Plexin D1 signaling pathways
drive the metastatic dissemination. Furthermore, the expression of Sema3E
in primary human colorectal tumors correlates with the formation of distant
metastases. This suggests that the expression of semaphorin 3E/Plexin D1
in human tumors represents an independent prognostic factor for patients
stratification. Furthermore, in preclinical models in vivo, this signaling
pathway driving tumor progression can be blocked by a modified variant
of Sema3E (UNCL-Sema3E). This molecule shows strong anti-angiogenic
and anti- metastatic activities. Finally, the receptor Neuropilin-1 controls
the signaling pathway mediated by EGFR, a major oncogene driving tumor
progression, targeted by innovative therapeutic approaches.
The elucidation of the functional
role and molecular mechanisms by
which Semaphorin genes control
the invasiveness of tumor cells and
the formation of metastases will
prompt the development of innovative diagnostic and therapeutic
approaches.
Selected references
Rizzolio S, Rabinowicz N, Rainero
E, Lanzetti L, Serini G, Norman J,
Neufeld G,Tamagnone L. Neuropilin1-dependent regulation of EGFreceptor signaling. Cancer Res. 2012,
72:5801-11
Tamagnone L. Emerging role of
semaphorins as major regulatory
signals and potential therapeutic
targets in cancer. Cancer Cell. 2012,
22:145-52
Casazza A, Kigel B, Maione F,
Capparuccia L, Kessler O, Giraudo E,
Mazzone M, Neufeld G,Tamagnone L.
Tumour growth inhibition and antimetastatic activity of a mutated furinresistant Semaphorin 3E isoform
EMBO Mol Med. 2012, 4:234-50
Projects and goals
(i) To identify and to characterize novel semaphorin signaling pathways in
control of tumor progression, by regulating tumor cell behavior and/or
the stromal microenvironment; (ii) to understand the molecular mechanisms that mediate semaphorin functions
in cancer, including the identification of new signal transducers associated with receptor complexes , (iii) to
validate new molecular tools specifically targeting the signaling pathways
Team
Michael Rehman, Sabrina Rizzolio, Lorena Capparuccia, Chiara Battistini, Gabriella Cagnoni, Gurrapu
Sreeharsha, Massimo Accardo
Uncle-Sema3E is an
engineered form of
Semaphorin 3E, which
concomitantly inhibits
tumor angiogenesis and
metastasis, by dismantling
receptor complexes at the
cell surface.
14 | The mechanisms of cancer onset and progression
Dynamic control of cell adhesion in the ‘normalization’ of tumor
blood vessels
The pharmacological modulation
of integrin function can be therapeutically exploited to improve the
biodistribution of anti-neoplastic
drugs and counteract the hypoxiadriven metastatic dissemination of
cancer cells.
Selected references
Valdembri D, Serini G. Regulation of
adhesion site dynamics by integrin
traffic. Curr. Opin. Cell Biol. 2012,
24:582-91
Sandri C, Caccavari F, Valdembri D,
Camillo C, Veltel S, Santambrogio
M, Lanzetti L, Bussolino F, Ivaska
J, Serini G. The R-Ras/RIN2/Rab5
complex controls endothelial cell
adhesion and morphogenesis via
active integrin endocytosis and Rac
signaling. Cell Res. 2012, 22:1479501
Maione F, Molla F, Meda C, Latini R,
Zentilin L, Giacca M, Seano G, Serini
G, Bussolino F, Giraudo E.
Semaphorin 3A is an endogenous
angiogenesis inhibitor that blocks
tumor growth and normalizes
tumor vasculature in transgenic
mouse models. J. Clin. Invest. 2009,
119:3356-72
Guido Serini MD PhD
Laboratory of Cell Adhesion Dynamics
[email protected]
Rationale
The binding of cells to the surrounding extracellular matrix is mediated by
a class of adhesive receptors known as integrins, which can assume active
or inactive conformations, respectively characterized by high or low affinity
binding to the extracellular matrix.
Results
We showed how the modulation of integrin conformation and traffic is a
key aspect of the molecular signals through which semaphorins control via
their receptors plexins the correct morphogenesis of the vascular system; an
abnormal control of these signals underpins the alterations that characterize
tumor blood vessels. Finally, we found out how restoring the physiological
inhibitory control of integrins by semaphorin can effectively prevent such
vascular abnormalities, thus improving blood supply and penetration of anti
-neoplastic as well as counteracting metastatic dissemination.
Projects and goals
Characterization of the mechanisms and molecular determinants responsible
for: (i) inhibition of the adhesive function of endothelial cells by the secreted
semaphorins; (ii) the selective control of active integrin traffic in endothelial
cells. Molecular variants of semaphorin endowed with greater affinity for the
receptor will be generated by mutagenesis and their potential therapeutic
efficacy will be experimentally tested in transgenic models of cancer.
Team
Chiara Camillo, Noemi Gioelli, Chiara Sandri
‘Semaphoring’ blood vessel cell adhesion
The mechanisms of cancer onset and progression | 15
New targets for the anti-angiogenic therapy
Enrico Giraudo PhD
Laboratory of Transgenic Mouse Models
[email protected]
Rationale
Some of the proteins that regulate the interaction between cell-matrix
and cell-cell, such as Class 3 Semaphorins (Sema3s), are involved in the
regulation of tumor angiogenesis and in the formation of metastasis,
therefore, representing new targets for anti-angiogenic therapy
Results
Employing preclinical mouse models of cancer we described for the first time
Sema3A as an endogenous angiogenesis and tumor inhibitor that is turn off
during cancer progression. Sema3A re-expression by somatic gene transfer
into different tumor types, significantly impaired angiogenesis, blocked
tumor growth and metastasis formation, by normalizing the vasculature
and inhibiting cancer hypoxia. Recently we demonstrated that the treatment
of several mouse models of cancer with Sema3A, by inducing tumor blood
vessel normalization and improving cancer tissue oxygenation, efficiently
overcame the evasive resistance to the anti-angiogenic therapy induced by
clinically approved drugs, such as Sunitinib and DC101, blocking metastasis
and enhancing the survival. Moreover, Sema3A, improving vessel perfusion,
significantly improved the delivery of chemotherapeutic drugs to the tumors
and enhanced their efficacy.
Projects and goals
(i) to employ Sema3A super-agonists mutants as new compounds to
overcome the evasive resistance to the anti-angiogenic therapies, to halt
metastasis formation and to normalize tumor vessels; (ii) to assess the
efficacy of combining Sema3s or other axon guidance cues delivery with
conventional anti-angiogenic drugs to block metastases dissemination using
different mouse models of cancer; (iii) to identify the mechanisms by which
Semas, their receptors and other axon guidance cues regulate “stroma”
normalization, tumor invasiveness and metastases formation.
Team
Federica Maione, Stefania Capano, Donatella Regano
16 | The mechanisms of cancer onset and progression
The better understanding of the
anti-metastatic and normalizing
effects of Sema3s on tumor blood
vessels, will allow to design
new strategy to overcome the
resistance to the anti-angiogenic
therapy.
Selected references
Serini G, et al. Class 3 semaphorins:
physiological vascular normalizing
agents for anti-cancer therapy. J.
Intern. Med. 2013, 273:138-55.
Maione F,et al. Semaphorin 3A
overcomes cancer hypoxia and
metastatic dissemination induced by
antiangiogenic treatment in mice. J.
Clin.Invest. 2012, 122:1832-48.
Meda C,et al. Sema4A exerts a
pro-angiogenic effect by enhancing
VEGF-A expression in macrophages. J.
Immunol. 2012, 188:4081-92
Casazza A,et al. Tumour growth
inhibition and
anti-metastatic activity of a mutated
furin-resistant Semaphorin 3E
isoform. EMBO Mol Med. 2012,
4:234-50
Role of membrane receptor endocytosis in the dissemination of
metastatic cells.
Knowing the mechanisms that
control the downregulation of receptors involved in metastatic cell
dissemination provides the rationale for the generation of innovative
anti -neoplastic drugs.
Selected references
Palamidessi A, Frittoli E, Ducano N,
Offenhauser N, Sigismund S, Kajiho
H, Parazzoli D, Oldani A, Gobbi M,
Serini G, Di Fiore PP, Scita G, Lanzetti
L. The GTPase-activating protein RNtre controls focal adhesion turnover
and cell migration. Curr Biol. 2013,
23:2355-64.
Lanzetti L. A novel function of Rab5
in mitosis. Small GTPases. 2012,
3:168-72.
Serio G, Margaria V, Jensen S, Oldani
A, Bartek J, Bussolino F, Lanzetti L.
Small GTPase Rab5 participates
in chromosome congression
and regulates localization of the
centromere-associated protein
CENP-F to kinetochores. Proc Natl
Acad Sci U S A. 2011, 108:17337-42
Letizia Lanzetti PhD
Laboratory of Membrane Trafficking
[email protected]
Rationale
Metastatic cancer cells, in order to spread, must activate a process known
as invasive growth. The invasive growth program relies on the activation of
plasma membrane receptors that are essential for proliferation and migration
of metastatic cells in the surrounding tissues. Among these receptors,
a key role is played by the family of adhesive receptors integrins and by
the tyrosine kinase receptor Met. Several molecules finely regulate their
activation and localization to the plasma membrane. Our unit studies some
of these proteins, such as the small GTPase Rab5 and its effectors, whose
function is to control the endocytosis of the receptors, their removal from the
cell surface, and their downregulation.
Results
(i) We have isolated a novel regulator of growth factor-mediated cell migration.
This molecule, named USP6NL, by turning off the GTPase Rab5, inhibits the
endocytosis of adhesive receptors strongly reducing cell motility; ( ii ) we
have also identified a novel function of Rab5 in the correct segregation of
chromosomes during cell division .
Projects and goals
(i) To identify the molecular mechanisms that control the traffic of integrins
and of the Met receptor in cancer cells characterized by increasing degrees
of invasiveness; (ii) to study the effects caused by antibodies and catalytic
inhibitors in the endocytosis and downregulation of tyrosine kinase receptors;
(iii) to characterize the role of Rab5 and of its molecular network during the
division of normal and cancer cells.
Team
Emanuela Pupo, Nadia Ducano
Figure 1. Recruitment of the Rab5 GTPaseactivating protein RN-tre to adhesive sites.
The mechanisms of cancer onset and progression | 17
From neuronal biology to neoplastic progression
Marco Arese PhD
Laboratory of Neurovascular Biology
[email protected]
Rationale
We want to exploit the presence of proteins of nervous origin in the
“integrated” tumor tissue, and all the relative knowledge deriving from the
field of neurobiology, to bring new therapeutic tools in oncology. Neurexin
and Neuroligin, two neuronal synaptic proteins, are the main objectives.
Results
Neurexin and Neuroligin are produced not only by neurons but also by
cells of the vascular system, and they promote the formation of new blood
vessels in experimental models of embryonic development and tumor
angiogenesis. We generated a monoclonal antibody against an isoform of
Neurexin that inhibits angiogenesis. Functionally, Neurexin and Neuroligin
cooperate with VEGFA, the most studied pro-angiogenic factor, and with the
adhesive receptor integrin alpha 6 beta 1, an important mediator of tumor
angiogenesis. We also showed that Neurexin and Neuroligin are produced by
tumor cells and that the expression of Neuroligin is strongly reduced during
colorectal cancer ( CRC) progression. The reconstitution of its expression
in CRC cells restricts the growth of the tumor. These data support the
hypothesis that Neuroligin acts as a tumor suppressor in CRC.
The identification of ‘molecular
keys’ that mediate the relationship
between tumor cells, blood
vessels and nerves will contribute
to the definition of a new class of
therapeutic targets.
Selected references
Rissone A, Foglia E, Sangiorgio L,
Cermenati S, Nicoli S, Cimbro S,
Beltrame M, Bussolino F, Cotelli
F, Arese M. The synaptic proteins
neurexin and neuroligin synergize with
extracellular matrix-binding vascular
endothelial growth factor a during
zebrafish vascular development.
Arterioscler Thromb Vasc
Biol. 2012, 32:1563-72.
Bottos A, Rissone A, Bussolino F,
Arese M. Neurexins and neuroligins:
synapses look out of the nervous
system. Cell Mol Life Sci. 2011,
68:2655-66.
Rissone A, Sangiorgio L, Monopoli
M, Beltrame M, Zucchi I, Bussolino F,
Arese M, Cotelli F. Characterization of
the neuroligin gene family expression
and evolution in zebrafish. Dev Dyn.
2010,239:688-702.
Projects and goals
We intend to : (i) define the cellular roles of Neurexin and Neuroligin in
nerves, blood vessels and tumor cells; (ii) define the role of Neurexin and
Neuroligin as mediators of communication between the tumor and its
environment in two contexts : a) in the release of paracrine factors that
modulate angiogenesis and neurogenesis b ) in the direct contacts between
tumor cells and nerve cells (neuroneoplastic synapses) (iii) determine the
molecular pathway by which Neurexin and Neuroligin play their roles in
tumor or vascular cells, and the extent to which the neuronal machinery is ‘
recruited ‘ by these cells.
Team
Margherita Pergolizzi, Laura Bizzozero, Elena Riccitelli
Tumor cells associated to a nervous axon
in a perineural invasion model
18 | The mechanisms of cancer onset and progression
Cellular and molecular mechanisms sustaining tumor angiogenesis
All target therapies, including
antiangiogenic therapies, are far
from the wished results. However
antiangiogenic regimens are an
important tool for solid tumor
treatment. Our studies aim at
understanding the complexity of
angiogenic process in physiology.
Selected references
Bussolino F, Giraudo E, Serini G. Class
3 semaphorin in angiogenesis and
lymphangiogenesis. Chem Immunol
Allergy. 2014, 99:71-88
Marchiò S, Astanina E, Bussolino F.
Emerging lymphae for the fountain of
life. EMBO J. 2013,32:609-11
Napione L et al. IL-12-dependent
innate immunity arrests endothelial
cells in G0-G1 phase by a p21(Cip1/
Waf1)-mediated mechanism.
Angiogenesis. 2012, 15:713-25
Marchiò S, et al. A complex of alpha6
integrin and E-cadherin drives liver
metastasis of colorectal cancer cells
through hepatic angiopoietin-like 6.
EMBO Mol Med. 2012,4:1156-75
Federico Bussolino MD
Laboratory of Vascular Oncology
[email protected]
Rationale
Tumor angiogenesis is a validated target to fight solid tumor. However,
clinical results are far from the expectations coming from animal models
that clearly demonstrated that the inhibition of VEGF pathway halts tumor
progression. In this context our main goal is to study the circuits between
cancer and vascular cells to obtain new knowledge useful for envisaging the
therapeutic approaches.
Results
(i) PLX4720, a specific inhibitor of the mutated kinase BRAFV600E, promotes
vascular normalization and disease stabilization in preclinical models of
colorectal cancers and melanomas; (ii) during embryo development VEGFR2
expression and activity is regulated by membrane proteins, including
Neuropilin-1 and integrins and a specific co-regulatory mechanism occurring
in embryonic stem cells drives the differentiation towards vascular or neural
cell compartment; (iii) by combining bioinformatics and “gene-silencing”based approaches we identified Tfeb, as a key transcription factor involved
in epithelial-mesenchymal and in endothelial-mesenchymal transitions; (iv)
VEGFR2 and Tie-2, which is the receptor for angiopoietins, form different
complexes with integrins, which modulate the temporal and spatial signalling
responses.
Projects and goals
(i) To study the circuits between stroma and cancer cells in 3D cultures (ii) to
analyse tumour growth in mouse models carrying fibroblasts or endothelial
cells genetically modified; (iii) to analyse by systems biological techniques
of VEGF network, to identify new druggable targets ; (iv) to analyse the
transcriptome of stroma and vascular cells isolated from cancer tissues,
which do not respond to anti-angiogenic; (v) to identify of the methylome
in models of resistance to anti-angiogenic therapies; (vi) to study the role
of mixed regulatory circuits between transcription factors, microRNAs and
long-non coding RNAs in tumour.
Team
Elena Astanina, Valentina Comunanza, Gabriella Doronzo, Lucia Napione,
Alessio Noghero, Davide Corà, Maria Alvaro, Anna Gualandris
The mechanisms of cancer onset and progression | 19
Cell migration in tumor angiogenesis and invasion
Luca Primo PhD
Laboratory of Cell Migration
[email protected]
Rationale
To develop strategies able to counteract the metastatic dissemination we want
to define molecular mechanisms that may differentiate invasive cancer cells
from their non-motile counterparts, and the relationship between tumour
and non-tumour cells during cell migration. Cancer cells spread from the
initial site of tumour growth acquiring an invasive phenotype characterized
by both the loss of cell-cell interactions and increased cell motility. Vascular
cells migrate into tumor mass forming new vessels in a process called tumor
angiogenesis.
Results
We demonstrated that PDK1, the pivotal molecule in the PI3K signalling
pathway, was necessary for endothelial and breast cancer cell migration.
Now we are characterizing the pathway linking PI3K/PDK1 to the actin
cytoskeleton, integrins and contraction, and how these pathways regulate
motility in carcinoma and endothelial cells. We showed that integrin alpha6 is
upregulated during tumor angiogenesis and it was involved in the endothelial
sprouting process. We developed new three-dimensional culture systems that
in combination with conventional cell biology approaches, allow studying
collective and directional cell migration.
The identification of molecular
mechanisms involved in tumor
cell migration will allow to prevent
the metastatic dissemination by
pharmacologic inhibition.
Selected references
Seano G, Chiaverina G, Gagliardi
PA, di Blasio L, Sessa R, Bussolino
F, Primo L. Modeling human tumor
angiogenesis in a three-dimensional
culture system.
Blood. 2013, 121:129-37
Gagliardi PA, et al. Phosphoinositidedependent kinase 1 controls breast
tumor growth in a
kinase-dependent but Aktindependent manner. Neoplasia.
2012, 14:719-31.
Primo L, et al.Increased expression
of alpha6 integrin in endothelial
cells unveils a proangiogenic role for
basement membrane.
Cancer Res. 2010,70:5759-69.
Sessa R, et al.The miR-126 regulates
angiopoietin-1 signaling and vessel
maturation by targeting p85. Biochim
Biophys Acta. 2012, 1823:1925-35.
Projects and goals
The focus of our research is to understand why and how endothelial and cancer
cells spread through the body. Specific aims: (i) to study the role of PI3KPDK1 signalling in tumor angiogenesis and invasion; (ii) to characterize the
molecular mechanisms activated by PI3K-PDK1 during cell migration; (iii) to
develop and improve experimental 3D models of collective cell migration; (iv)
to provide integrative mathematical and computational models simulating
the morphogenetic and invasive processes of vascular and tumor; (v) to
decipher the role of vascular basement membrane and pericytes in tumor
angiogenesis and invasion;
Team
Laura Di Blasio, Alberto Puliafito, Giulia Chiaverina, Paolo Gagliardi
Endothelial cells sprout from human umbilical
arterial rings embedded in extracellular matrix
gel, forming new capillary structures.
20 | The mechanisms of cancer onset and progression
The cancer microenvironment
The exploration of the interactions
between metastasis and the
healthy tissue will identify
molecules with diagnostic or
prognostic value.
Selected references
Loi M, et al. Novel phage displayderived neuroblastoma-targeting
peptides potentiate the effect of drug
nanocarriers in preclinical settings. J
Control Release 2013, 170:233-41.
Marchiò S, Astanina E, Bussolino F.
Emerging lymphae for the fountain of
life. EMBO J 2013, 32:609-11.
Marchiò S, et al.
A complex of alpha 6 integrin and
E-cadherin drives liver metastasis
of colorectal cancer cells through
hepatic angiopoietin-like 6. EMBO
Mol Med 2012, 4:1156-75.
Serena Marchiò PhD
Laboratory of Cancer Microenvironment
[email protected]
Rationale
While much is known about the biology of the cancer cell as an autonomous
entity, the molecular network that drives the crosstalk between tumor cells
and the host tissue remains a largely unexplored area. In particular, in
metastatic colorectal cancer these interactions play a key role in the early
development stages of the disease.
Results
Two adhesion molecules, i.e. E-cadherin and a6 integrin, have been identified
as a new receptor complex expressed on the surface of cells of metastatic
colorectal cancer (CRC). This receptor binds specifically to a soluble protein
produced by the healthy liver, the angiopoietin-like factor 6, driving the
recognition between the two tissues in the steps of homing, engraftment
and colonization. The activation of this molecular circuitry also leads to the
induction of a transcriptional program that provides cancer cells with stem
cell features (block of differentiation, motility, alteration of proliferative and
morphological parameters), thus increasing their metastatic potential.
Projects and goals
To provide the ‘signature’ of other extracellular proteins that drive cell-cell
and cell-matrix interactions in the microenvironment of metastatic CRC.
This ‘signature’ will be exploited to identify protein markers useful for the
development of diagnostic tools. Such markers, at the same time, may
represent potential targets for new biological therapies, particularly where
the presence of specific mutations makes patients non-responsive to current
treatment regimens.
Team
Alice Bartolini
The mechanisms of cancer onset and progression | 21
Mechanisms of escape from anti-angiogenic therapy
Paolo Michieli PhD
Laboratory of Cancer Metabolism
[email protected]
Rationale
Anti-angiogenic therapy is one of the most utilized biological therapies
for the treatment of metastatic colorectal carcinoma. Despite the initial
enthusiasm clinical trials have shown that anti-angiogenic agents are less
effective than anticipated. The fundamental biologic problem behind these
clinical observations resides in the resilience of tumor cells, which know how
rapidly adapt to unfavorable environmental conditions. Hypoxia and glucose
or amino acid deprivation themselves may induce an adaptive response
driving cancer cells to become more aggressive and metastatic.
Results
A previous study dentified the HGF/MET pathway as an important regulator
of cellular invasiveness in response to hypoxia. Based on this study, we
hypothesized that this molecular mechanism may be responsible for invasive
resistance to anti-angiogenic therapy of colorectal carcinoma. In a number
of orthotopic mouse models of colorectal cancer we show that: (i) treatment
with angiogenesis inhibitors cause activation of the HGF/MET pathway in the
tumor; (ii) in the presence of HGF, angiogenesis inhibitors lose their efficacy
and induce the formation of metastases; (iii) treatment with HGF/MET
inhibitors increase tumor sensitivity to anti-angiogenic therapy and prevents
the occurrence of metastases consequent to angiogenesis inhibition.
Projects and goals
While much emphasis has been put on the consequences of tumor hypoxia,
little relevance has been attributed to the role of nutrient deprivation. Ongoing
experiments indicate instead that sugar and amino acid metabolism plays a
relevant role in determining response or resistance to anti-tumor therapies,
and in particular to anti-angiogenic therapy. The research will focus onto
gaining new insights into these biochemical pathways in preclinical models,
investigating the link between oncogene signal transduction pathways and
metabolism on one hand, and the effect of anti-metabolic drugs on tumor
growth and invasion on the other.
Team
Manuela Cazzanti, Federica Linty, Alessia Mira, Virginia Morello
22 | The mechanisms of cancer onset and progression
The development of novel
approaches such as anti-metabolic
therapy can open new avenues for
the treatment of the aggressive
forms of colorectal cancer.
Selected references
Michieli P, Di Nicolantonio F. Targeted
therapies: Tivantinib - a cytotoxic
drug in MET inhibitor’s clothes? Nat
Rev Clin Oncol. 2013, 10:372-4.
Basilico C, Pennacchietti S, Vigna E,
Chiriaco C, Arena S, Bardelli A,
Valdembri D, Serini G, Michieli
P. Tivantinib (ARQ197) displays
cytotoxic activity that is independent
of its ability to bind MET.
Clin Cancer Res. 2013;19:2381-92.
Michieli P. Hypoxia, angiogenesis and
cancer therapy: to breathe or not to
breathe? Cell Cycle. 2009, 8:3291-6
Galluzzo M, et al. Prevention of
hypoxia by myoglobin expression
in human tumor cells promotes
differentiation and inhibits
metastasis. J Clin Invest. 2009,
119:865-75.
Research topic 2
From Molecular Biology to “Precision Medicine”
Research topic 2 is the scientific core on which the projects of most laboratories of the Institute are focused.
Advances in genome sequencing and expression analysis has made possible to quickly identify genetic
alterations with a potential “driverl” role in tumor development, with an unprecedented informative power.
Thanks to these studies, today it is possible to classify tumors, not only on the basis of their site of origin and
histopathological features, but also – and especially – by the identification of the genetic lesions that support
their growth and that, for this reason, provoke tumor death when deactivated by targeted therapies. However,
the contribution of each lesion to the transformed phenotype remains elusive. Moreover, knowledge is still
insufficient on the mechanisms that control the lack of response to targeted therapies, even in the presence of a
molecular target (primary resistance), as well as on the mechanisms that lead to progressive attenuation of the
response after a prolonged treatment (acquired resistance). Translational Research is a multi-disciplinary task
based on the expertise of a new generation of scientists, specifically trained to translate molecular information
into more effective treatments. The goals are ambitious: to integrate the traditional prognostic and diagnostic
factors with a very detailed characterization of the genetic and functional alterations of the tumor; to identify
new malfunctioning regulatory pathways in cancer; to isolate and study the cancer stem cells; to develop new
preclinical platforms that can reliably disclose – and understand in detail – the prospective results of clinical
practice. The generation of this kind of knowledge is instrumental to instructing clinical trials that will be no
longer based on empirical information but on a strong rational connotation.
Research Topic 2 concerns:
2.1. Oncogenes and growth factors
2.2. Genes responsible for response to antineoplastic drugs
2.3. Preclinical models of “personalized” therapies
2.4. Resistance to targeted therapies
From Molecular Biology to “Precision Medicine” | 23
The Institute organizes a bi-annual International Conference on Molecular Clinical Oncology
The first meeting “Invasive growth a Genetic Programme for Stem Cells and Cancer” was held in September 2009, the second “A Burgeoning
Medical Science” was held in May 2011, the third “Precision Medicine” in October 2014.
www.cancercoop.org
24 | From Molecular Biology to “Precision Medicine”
Oncogenes involved in the invasive growth.
The genetic and molecular biology
beyond the metastatic process is
largely unknown. It is mandatory to
identify and to validate therapeutic
targets to develop the long-sought
(and still missing) effective
therapies.
Selected references
Benvenuti S, Gentile A, Lazzari L,
Arnesano A, Trusolino L, Comoglio
PM. An ‘in-cell trial’ to assess the
efficacy of a monovalent anti-MET
antibody as monotherapy and in
association with standard cytotoxics.
Mol Oncol. 2014, 8:378-88
Vigna E, et al.Targeted therapy
by gene transfer of a monovalent
antibody fragment against
the Met oncogenic receptor. J Mol
Med (Berl). 2014, 92:65-76
Gentile A, Lazzari L, Benvenuti S,
Trusolino L, Comoglio PM. Ror1 is a
pseudokinase that is crucial for Metdriven tumorigenesis. Cancer Res.
2011, 71:3132-41.
Benvenuti S, Lazzari L, Arnesano A,
Li Chiavi G, Gentile A, Comoglio PM.
Ron kinase transphosphorylation
sustains MET oncogene addiction.
Cancer Res. 2011 ;71:1945-55.
Paolo Comoglio MD
Laboratory of Exploratory Research
[email protected]
Rationale
Growing evidence prompted us to hypothesize that the metastatic process
involves members of the gene ‘super-family’ of tyrosine kinase receptors
for ‘scatter factor’, homologues to Met oncogene (Ron, Axl, Mer and Tyro).
Recently, other poorly characterized genes of the family have been identified,
Ror1 and Ror2, that can possibly interfere with the response to drugs directed
against Met (entered in the clinic), generating resistance.
Results
In the past we have shown that the Met oncogene encodes the receptor for
the ‘scatter factor’ HGF. A series of studies –performed for two decades in
this and other laboratories- revealed the involvement and the importance of
this oncogene in human cancers, demonstrating its key role in the control
of ‘invasive growth’, a genetic program driving the metastatic process.
We contributed to the development of drugs inactivating the Met tyrosine
kinase: either chemical inhibitors or monoclonal antibodies. These drugs
inactivate cancer stem cells in preclinical models of glioblastoma, colorectal
and gastric carcinomas, and provides promising results in clinical trials.
Projects and goals
We are now working on the characterization of tyrosine kinase receptors
of the Met oncogene family (Ron, Axl, Mer and Tyro, Ror1-2) at genetic,
biochemical and functional level. In particular, we are studying their possible
interference -positive or negative- with the intracellular signaling triggered by
Met during the execution of the invasive growth program. Emphasis is given
to the study of an hyper-metastatic syndrome, the so-called CUP, metastatic
cancer from unknown primary origin.
Team
Cristina Basilico, Silvia Benvenuti, Alessandra Gentile, Maria Rita Virzì
Mechanisms underlying down-regulation and ‘shedding’.of the Met
oncogenic receptor upon binding of a specific therapeutic antibody
From Molecular Biology to “Precision Medicine” | 25
Preclinical models of oncogene ‘addiction’
Livio Trusolino MD
Laboratory of Precision Medicine
[email protected]
Rationale
It has now become increasingly clear that some tumors are dependent on
one ‘dominant’ genetic lesion for their relentless growth and survival, so that
therapeutic inactivation of this lesion results in tumor regression (‘oncogene
addiction’). However, this acquired knowledge has been translated into
effective treatments very slowly, in part due to difficulty in predicting how the
complex mutational background of human cancers can influence the activity
of the dominant oncogene, thus modifying response to therapies.
Results
In the past years we have identified ‘private’ signaling partners of the Met
tyrosine kinase, which are able to fine-tune ‘public’ signaling outputs and to
confer signal specificity to Met-triggered transduction pathways. We have also
introduced the concept of ‘oncogene expedience’, as opposed to ‘oncogene
addiction’, to explain tumor contexts in which Met acts as an adjuvant prometastatic gene rather than as a genetic determinant of the transformed
phenotype. Finally, we have demonstrated that patient-derived xenografts
from metastatic colorectal carcinomas (‘xenopatients’) reliably mimic
disease response in humans and prospectively recapitulate biomarker-based
case stratification. By this approach, we have identified the HER2 oncogene
as a predictor of resistance to anti-EGFR antibodies and as a predictor of
response to combinatorial therapies against HER2 and EGFR in this tumor
setting. In the same vein, we have recently found that amplification of the
MET oncogene correlates with resistance to anti-EGFR therapies and is an
effective therapeutic target in KRAS wild-type colorectal tumors.
Projects and goals
Our projects aim at exploring the mechanisms that underlie tumor addiction
to defined genetic lesions, with a special emphasis on colorectal cancer. To this
objective, we will use different technological platforms (phosphoproteomics,
gene expression profiling, DNA sequencing, gene copy number analysis) and
various experimental settings (cell lines, ‘xenopatients’, and patient-derived
cancer cell lines).
Team
Andrea Bertotti, Barbara Lupo, Francesco Galimi, Francesco Sassi, Giorgia
Migliardi, Francesca Cottino, Simonetta Maria Leto, Eugenia Zanella.
26 | From Molecular Biology to “Precision Medicine”
We aim to identify ‘dominant’
genetic aberrations that drive
tumorigenesis and put them in the
context of concurrent ‘recessive’
alterations that may act as
modifiers of response to targeted
therapies.
Selected references
Trusolino L, Bertotti A. Compensatory
pathways in oncogenic kinase
signaling and resistance to targeted
therapies: six degrees of separation.
Cancer Discov. 2012, 2:876-80.
Bertotti A, et al. A molecularly
annotated platform of patient-derived
xenografts (“xenopatients”) identifies
HER2 as an effective therapeutic
target in cetuximab-resistant
colorectal cancer. Cancer Discov.
2011, 1:508-23.
Bertotti A, et al. Inhibition of Src
impairs the growth of met-addicted
gastric tumors. Clin Cancer Res.
2010, 16:3933-43.
Bertotti A, et al. Only a subset of
Met-activated pathways are required
to sustain oncogene addiction. Sci
Signal. 2009, 2:ra80.
The puzzling oncosuppressive function of oncogenes
Identification of novel therapeutic
targets and predictive biomarkers
responsive to chemotherapy or
targeted drugs in ovarian cancer
Selected references
Pavan S, et al. HSP27 is required for
invasion and metastasis triggered
by hepatocyte growth factor. Int J
Cancer. 2014, 134:1289-99.
Lorenzato A, et al. AKT activation
drives the nuclear localization
of CSE1L and a pro-oncogenic
transcriptional activation in ovarian
cancer cells. Exp Cell Res. 2013,
319:2627-36.
Pavan S, Olivero M, Corà D, Di Renzo
MF. IRF-1 expression is induced by
cisplatin in ovarian cancer cells
and limits drug effectiveness. Eur J
Cancer. 2013, 49:964-73.
Bardella C, et al. Cells lacking the
fumarase tumor suppressor
are protected from apoptosis
through a hypoxia-inducible factorindependent, AMPK-dependent
mechanism. Mol Cell Biol. 2012,
32:3081-94.
Maria Flavia Di Renzo MD
Laboratory of Cancer Genetics
[email protected]
Rationale
Intrinsic tumor suppression of oncogenes, although puzzling, is an actual
self-defeating program that has evolved in cells to respond to the elevation in
signal intensity accompaniyng oncogenic activation. This program does not
confer a selective advantage and thus it is hidden in cancer cells, but it might
be unleashed to commit cells to death.
Results
This laboratory has shown that the tyrosine kinase receptors elicit both
survival and death signals and that the latter can be exploited to kill cancer
cells. Using phosphoproteome and transcriptome approaches the laboratory
has identified a number of transducers and effectors of the pro death activity
of tyrosine kinase (TK) receptors. Among the transcriptional targets, some
-such as the product of the CSE1L/CAS gene- play specific roles in ovarian
cancer cells by killing and sparing the cells. Other signaling molecules have
been identified, which are necessary for cancer cells to tolerate DNA damage
and proliferative stress. Among these, the small heat shock protein of 27
KDa (HSP27) protects form the intrinsic oncosuppressive activities of TK
oncogenes and can be inhibited to kill cancer cells where these oncogenes
are activated.
Projects and goals
The goal of this Laboratory is to elucidate the mechanism of the death
signalling elicited by the tyrosine kinase oncogenes in ovarian cancers to
covert survival into death signals in these and other cancer cells. Therefore,
first we aim at understanding whether the pro-death effect could be elicited
by different TK oncogenes, such as MET, EGFR and HERII, activated by either
over-expression or mutation. Then, mediators and effectors of the pro-death
signaling of TK receptor should be identified. Subsequently, using an array
of assays in vitro and in vivo, the role of the identified molecules should be
validated to understand if these molecules might be targets for therapeutic
intervention.
Team
Annalisa Lorenzato, Martina Olivero, Jessica Erriquez, Daniele Musiani,
John David Konda, Erica Torchiaro
From Molecular Biology to “Precision Medicine” | 27
Cancer stem cells and resistance to standard
and targeted cancer therapies
Carla Boccaccio MD
Laboratory of Cancer Stem Cells Research
[email protected]
Rationale
Tumor tissues are structured according to a hierarchy that includes two main
components. At the hierarchy’s apex there is a (small) subpopulation of
‘cancer stem cells’ (CSC) able to self-renew, namely to proliferate endlessly,
and to relentlessly support tumor regeneration, growth, and dissemination.
At the hierarchy’s base there is an ample subpopulation of cells that, unlike
CSC, have limited proliferative ability, and tend to aberrantly differentiate
and die. This hierarchical model implies that, to cure the tumor, CSC must be
eradicated. This is a difficult task, because CSC are often inherently resistant
to therapies that so far have been successful against the hierarchical basis
of tumor cells.
Results
We showed that tumor cells resist to therapies that damage DNA through
activation of the Met oncogene. The latter encodes the tyrosine-kinase
receptor for HGF and controls ‘invasive growth’, a process featuring cell
protection against adverse microenvironmental conditions. In tumor cells
that underwent radiotherapy, Met is activated by molecular mechanisms that
monitor DNA damage (such as ATM protein) and activate a transcription
factor (NF-kB), responsible for a defense program against damage. This
program includes activation of Met, which promotes survival and ‘adaptive
resistance’ against irradiation. Thus Met mediates a molecular mechanism
of radioresistance, and provided a rationale to combine radiotherapy with
drugs targeting the oncogene.
Projects and goals
In CSC derived from colorectal cancer, glioblastomas and other tumor models,
we plan (i) to study whether Met controls the CSC ability to self-renew and
to disseminate from primary tumors, that is to form metastasis; (ii) to verify
whether the Met oncogene mediates resistance to irradiation and other DNA
damaging agents; (iii) to study whether specific agents targeting Met, such
as tyrosin-kinase inhibitors or monoclonal antibodies, alone or in association
with other conventional or targeted therapies, can help to eradicate CSC.
Team
Francesca De Bacco, Paolo Luraghi, Viola Bigatto, Antonio D’Ambrosio,
Francesca Orzan, Raffaella Albano, Elena Casanova, Elia Cipriano, Gigliola
Reato
28 | From Molecular Biology to “Precision Medicine”
To set up therapies targeted
to ‘cancer stem cells’, that are
cells that constitute the ‘roots
of tumors’, resist to chemo- and
radio-therapy, and, after these
conventional treatments, can
cause tumor relapse.
Selected references
Luraghi P, et al. MET signaling in
colon cancer stem-like cells blunts
the therapeutic response to EGFR
inhibitors.
Cancer Res. 2014, 74:1857-69
Boccaccio C and Comoglio PM. The
MET oncogene in glioblastoma stem
cells: implications as a diagnostic
marker and a therapeutic target.
Cancer Res. 2013, 73:3193-9.
De Bacco F, et al. The MET
oncogene is a functional marker of
a glioblastoma stem cell subtype.
Cancer Res. 2012, 72: 4537-50
De Bacco F, Luraghi P, Medico
E, Reato G, Girolami F, Perera T,
Gabriele P, Comoglio PM, and
Boccaccio C. Induction of MET by
ionizing radiation and its role in
radioresistance and invasive growth
of cancer. J Natl Cancer I. 2011,
103:645-661
Integrative genomics of cancer progression and
resistance to treatments.
The integration of molecular
profiles and clinical information
enables accurate determination of
cancer aggressiveness and response to treatment, to individualize
therapeutic approaches (precision
medicine)
Selected references
Isella C, et al. MACC1 mRNA levels
predict cancer recurrence after
resection of colorectal cancer
liver metastases. Ann Surg. 2013,
257:1089-95
Isella C, Renzulli T, Corà D, Medico E.
Mulcom: a multiple comparison
statistical test for microarray data in
Bioconductor. BMC Bioinformatics.
2011, 12:382.
Misale S et al. Emergence of
KRAS mutations and acquired
resistance to anti-EGFR therapy
in colorectal cancer. Nature.
2012,486:532-6.
Mira A, Isella C, Renzulli T, Cantarella
D, Martelli ML, Medico E. The GAB2
signaling scaffold promotes
anchorage independence and drives
a transcriptional response associated
with metastatic progression of breast
cancer. Oncogene. 2009, 28:4444-55
Enzo Medico MD
Laboratory of Oncogenomics
[email protected]
Rationale
Molecular biology focuses on the impact of individual genes on cancer.
Integrative genomics evaluates systematically, on large datasets, multiple
kinds of gene alterations, at the DNA, RNA and microRNA level. In this way
it is possible to study the regulatory networks of cancer and to identify the
key alterations that drive tumor progression and response or resistance to
specific treatments.
Results
We have defined molecular signatures in colorectal cancer (CRC), associated
to the involvement of the MET oncogene in hemostasis alterations and in
resistance to radiotherapy. We have characterized the MET-driven invasive
growth genetic program in embryonal liver progenitors, and found that
it is associated to metastatic propensity of hepatocellular cancinoma,
cholangiocarcinoma and other cancers. Through expression profiling of
white blood cells we have defined transcriptional signatures associated with
germline mutation of RAS pathway genes. We have identified a drug, already
under clinical testing, effective on about 10% of CRC, including BRAF and
KRAS mutatants. Finally, we have identified the MACC1 gene as a positive
predictor of early relapse in patients operated for liver-metastatic CRC.
Projects and goals
Identify and experimentally validate new therapeutic and prognostic
determinants of colorectal cancer. We aim (i) to complete preclinical
validation, in patient-derived xenograft tumors, of the efficacy of a new therapy
targeted on the ubiquitin ligase pathway, (ii) to validate in vitro and in vivo
the therapeutic relevance of a translocation potentially mediating resistance
to EGFR-targeted treatments; (iii) to define therapeutic and prognostic
relevance of aberrant mRNA/microRNA circuits in CRC subgroups; (iv) to
define molecular signatures associated to sensitivity or resistance of rectal
cancer to preoperative chemo-radiotherapy.
Team
Claudio Isella, Consalvo Petti, Gabriele Picco, Sara Erika Bellomo
From Molecular Biology to “Precision Medicine” | 29
Pharmacogenomics of colorectal cancer.
Federica Di Nicolantonio PhD
Laboratory of Pharmacogenomics
[email protected]
Rationale
Several approved conventional chemotherapeutic agents were originally
designed to act on cell replication or fundamental metabolic patways of
cancer cells. The mechanisms underlying the sensitivity of individual tumors
to chemotherapy have not yet been elucidated.
Results
The presence of BRAF oncogenic mutations is associated with increased
sensitivity to chemotherapeutic agents capable of inhibiting the proteasome.
The pharmacogenomic relationship between oncogenic BRAF and proteasome
inhibitors has been validated in several BRAF mutant colorectal cancer
cell lines, as well as in xenograft models. Mechanistically, we speculate
that BRAF-mutant cells may experience a non-oncogenic addiction to the
proteasome function because the protein degradation mediated by the
ubiquitin-proteasome system is needed to counterbalance the proteotoxic
stress induced by the mutant protein.
Projects and goals
Unveil and functionally validate synthetic lethal interactions that encompass
conventional chemotherapy with tumor epigenetic and genetic variants. We
propose: (i) to injvestigate the molecular mechanisms underlying response
(or resistance) to DNA alkylating agents in colorectal cancer; (ii) to evaluate
the role of genetic and epigenetic alterations in DNA repair genes; (iii) to
implement a novel quantitative assay to measure methylation of genes
implicated in DNA repair, both in tumor tissue as well in free circulating
tumor DNA
Team
Ludovic Barault, Daniele Oddo
Integrated molecular analysis of cancer samples to select the most
appropriate therapy.
30 | From Molecular Biology to “Precision Medicine”
The knowledge of specific molecular alterations in the tumor
DNA repair pathway could define
a novel context of susceptibility for
alkylating agents.
Selected references
Zecchin D, et al. BRAF V600E Is
a Determinant of Sensitivity to
Proteasome Inhibitors. Mol Cancer
Ther. 2013, 12:2950-61.
Valtorta E, et al. KRAS gene
amplification in colorectal cancer
and impact on response to EGFRtargeted therapy. Int J Cancer. 2013,
133:1259-65.
Prahallad A, et al. Unresponsiveness
of colon cancer to BRAF(V600E)
inhibition through feedback activation
of EGFR. Nature. 2012, 483:100-3.
Di Nicolantonio F, et al. Deregulation
of the PI3K and KRAS signaling
pathways in human cancer cells
determines their response to
everolimus. J Clin Invest. 2010,
120:2858-66
Personalized therapy and non-invasive molecular diagnostics of
colorectal cancer.
To define the genetic and molecular characteristics of the patients
in order to lead and check the
treatment of colorectal cancer.
Selected references
Misale S., et al. Emergence of KRAS
mutations and acquired resistance
to anti EGFR therapy in colorectal
cancer. Nature. 2012, 486:532-6
Misale S., et al. Blockade of EGFR
and MEK Intercepts Heterogeneous
Mechanisms of Acquired Resistance
to Anti-EGFR Therapies in Colorectal
Cancer.
Sci Transl Med. 2014, 6:224ra26
Bardelli A., et al. Amplification of
the MET Receptor Drives Resistance
to Anti-EGFR Therapies in Colorectal
Cancer. Cancer Discov. 2013, 3:658-7
Diaz LA Jr, Bardelli A. Liquid Biopsies:
Genotyping Circulating Tumor DNA.
J Clin Oncol. 2014, 32:579-86
Alberto Bardelli PhD
Laboratory of Molecular Genetics
[email protected]
Rationale
The findings that cancer is a genetic disease and that the combination of
molecular alterations in the genome of somatic cells is the engine of tumor
progression have revolutionized oncology and lead to the definition of the
idea of precision medicine in oncology. This project has been conceived to
develop this research topic using colorectal cancer (CRC) as experimental
model, to identify new therapies that target the genetic alterations from
which tumors are dependent for their growth.
Results
Over the past five years, our research program translated into the first case of
personalized treatment in metastatic colorectal cancer. At the moment, the
treatment of this disease is conducted by targeted therapy with monoclonal
antibodies (moAbs) that identify the EGFR receptor. However, these drugs
provide a significant clinical advantage in only 10% of patients. Using samples
from the clinic and innovative cell models, we showed that the CRC having
molecular alterations at the level of the effectors downstream EGFR (such
as KRAS, NRAS, BRAF) are resistant to treatment with antibodies directed
against EGFR. In parallel to the definition of tissue biomarkers, we developed
a cutting-edge technology that allows to identify oncogenic alterations in the
DNA released by neoplastic cells in the flow of blood.
Projects and goals
Our future goals concern the identification of new personalized treatments
for colorectal cancer through the study of the association between the
molecular characteristics of the single patients and the response/resistance
to treatment in preclinical models. With some coordination activities, our
group participates in clinical trials in which the hypotheses we put forward by
using preclinical models are experimentally evaluated in coorts of patients.
Within these studies, the response to treatment is also evaluated drawing
real-time the molecular profile of the patient through the liquid biopsy
approach described before.
Team
Sabrina Arena, Sebastian Hobor, Simona Lamba, Luca Lazzari, Sandra
Misale, Mariangela Russo, Beth Van Emburgh, Giulia Siravegna, Carlotta
Cancelliere, Benedetta Mussolin
From Molecular Biology to “Precision Medicine” | 31
Antibody gene transfer for ‘active’ targeted cancer immunotherapy
Elisa Vigna PhD
Laboratory of Gene Transfer
[email protected]
Rationale
Clinical evidence indicates that the MET oncogene plays a role in progression
of cancer toward metastasis and/or resistance to targeted therapies.
While mutations are rare, the common mechanism of MET activation is
overexpression, either by gene amplification (‘addiction’) or transcriptional
activation (‘expedience’). In both instances ligand-independent kinase
activation plays the major role in sustaining the transformed phenotype.
Currently available MET antibodies are directed against the receptor binding
site, behaving essentially as ligand (HGF) antagonist, and are ineffective in
ligand-independent activation.
Results
The monovalent chimeric MV-DN30 antibody, delivered as purified protein,
binds the fourth IPT extracellular domain and induces proteolytic cleavage
of MET, dramatically inhibiting downstream signaling pathways, in both
absence or presence of ligand. As an inventive approach, Mv-DN30 was
delivered by ‘gene therapy’ driven by a second generation bidirectional
lentiviral vector. In vitro, the antibody displayed a strong inhibition of ligandindependent invasive growth of MET ‘addicted’ cancer lines, and –notably- of
primary cells from a MET amplified gastric ca. patient. In vivo the antibody
strongly impaired the growth of a panel of MET ‘addicted’ human cancer
lines, xenotransplanted in nude mice lacking HGF. In patient-derived RAS
wt colorectal cancer xenografts, MET amplification was found to correlate
with resistance to anti EGFR therapy. By the gene therapy approach, direct
Mv-DN30 gene transfer in nude mice, intra-tumor or systemic, was followed
by a therapeutic response of MET addicted human glioblastomas and lung
carcinomas.
Development of novel therapeutic
strategies to generate, produce
and delivery monoclonal anti-cancer antibodies
Selected references
Vigna E, et al. Targeted therapy
by gene transfer of a monovalent
antibody fragment against the met
oncogenic receptor. J Mol Med (Berl).
2014, 92:65-76
Olwill SA, et al. A highly potent and
specific met therapeutic protein
antagonist with both liganddependent and ligand-independent
activity.
Mol Cancer Ther. 2013, 12:2459-71
Basilico C, et al. TIVANTINIB
(ARQ197) Displays cytotoxic activity
that is independent of its ability to
bind MET. Clinical Cancer Research
2013, 19:2381-92
Pacchiana G, et al. Monovalency
unleashes the full therapeutic
potential of the dn-30 anti-met
antibody.
J Biol Chem.2010, 285:36149-57
Projects and goals
To further develop the MV-DN30 antibody as a strong candidate for targeting
tumors sustained by a ligand-independent MET oncogenic activation, resulting
from MET amplification or mutations, and for overcoming resistance to antiEGFR therapies. These studies will also provide proof of concept for a gene
transfer immunotherapy strategy and encourage clinical studies with MvDN30.
Team
Simona Cignetto, Cristina Chiriaco, Lara Fontani
An example of therapeutic
efficacy of MET gene
therapy in a pre-clinical
model of GBM
32 | From Molecular Biology to “Precision Medicine”
Mechanisms of resistance to tyrosine kinase receptor inhibitors.
Design of strategies able to bypass
resistance to targeted therapies.
Selected references
Corso S. Giordano S. Cellautonomous and non-cellautonomous mechanisms of hgf/
met-driven resistance to targeted
therapies: from basic research to a
clinical perspective. Cancer Discov.
2013,3:978-92
Petrelli A, Perra A, Cora D, Sulas P,
Menegon S, Manca C, Migliore C,
Kowalik MA, Ledda-Columbano GM,
Giordano S, Columbano A. Mirna/
gene profiling unveils early molecular
changes and nrf2 activation in a rat
model recapitulating human hcc.
Hepatology. 2014, 59:228-41
Cepero V, Sierra JR, Corso S, Ghiso
E, Casorzo L, Perera T, Comoglio
PM, Giordano S. Met and kras gene
amplification mediates acquired
resistance to met tyrosine kinase
inhibitors. Cancer Res. 2010,
70:7580-90
Silvia Giordano MD
Laboratory of Molecular Biology
[email protected]
Rationale
In solid tumors, an altered regulation of tyrosine kinase receptors is rather
frequent, often associated to the acquisition of an aggressive phenotype.
The initial enthusiasm for the efficacy of therapies targeted to these
receptors is challenged by the lack of response in a percentage of patients
(primary resistance) and by the onset of resistance to treatment (secondary
resistance).
Results
We have been studying the mechanisms that provoke resistance to targeted
therapies against MET and EGFR receptors. We have recently observed that
Met amplification can provoke resistance to anti-EGFR therapies in colorectal
cancer; simultaneous inhibition of Met and EGFR is able to reactivate the
response. We have also identified molecular mechanisms that make tumor
cells resistant to the treatment with kinase MET inhibitors or with specific
monoclonal antibodies.
Projects and goals
Investigation of the molecular mechanisms that make cancer cells insensitive
to molecular targeted therapies. We will focus our attention mainly on gastric
carcinoma; recent studies showed that more than one third present FGFR2,
HER2, EGFR, MET or KRAS gene amplification. We are creating a bank of
“xenopatiens”, to analyze the molecular complexity of gastric tumor, to
identify therapeutic targets and to validate therapeutic strategies.
Team
Simona Corso, Elena Ghiso, Cristina Migliore, Annalisa Petrelli, Margherita
Pergolizzi, Maria Apicella
Tumor cells that acquired
resistance to MET inhibitors display
MET amplification (FISH analysis).
From Molecular Biology to “Precision Medicine” | 33
34 | From Molecular Biology to “Precision Medicine”
Research Topic 3
Investigational Clinical Oncology
Over the past few years, the improved knowledge on the biological, genetic and molecular heterogeneity of tumors,
together with the development of pharmacological technologies, allowed the identification of molecular targets
for novel therapeutic strategies. This fast process led to the overall reconsideration of classical approaches to
clinical oncology, traditionally oriented toward design of treatment cancers irrespectively from the biological
and genetic peculiarities that can make each tumor a pathology on its own. The identification of patients
likely to respond to specific treatments according to the presence of relevant molecular targets (personalized
medicine) and based on the expression of potential markers of sensitivity or resistance, needs clinical studies
that result from a constant and productive interaction among the professionals with a significant background
in the various disciplines.The goal of the “Investigational Clinical Oncology” team is to increase the therapeutic
index of molecular targeted drugs, by the identification and clinical validation of biomarkers of sensitivity/
resistance. This goal is pursued through the development of research programs aimed at designing hypothesisdriven clinical trials that directly derive from the Institute biological, genetic and molecular research. In order
for these tasks to be implemented, an ad-hoc organizational structure favours the interchange and the synergy
among preclinical researchers, oncologists and pharmaceutical companies – which are the potential providers
of new drugs for clinical trials. Another INCO’s goal will be the promotion of a clinical research culture based
on the knowledge of molecular biology and tumor genetics, and particularly of the mechanisms of sensitivity
or resistance to molecular targeted drugs. This organization is instrumental to the referral of patients for
admission into top-priority clinical trials.
Research Topic 3 is focused on:
3.0 Rational design of clinical trials for targeted drugs.
Investigational Clinical Oncology | 35
HERACLES and ARES:
trials for the ‘Precision Medicine’ of Cancer.
Silvia Marsoni MD
Unit of Clinical Trials
[email protected]
Rationale
Understanding of the cancer genome is driving the transition from a
morphology-based to a genetics-based cancer taxonomy. For many targeted
treatments the molecular features of a patient’s cancer can predict the
likelihood of clinical benefit, independently from the organ of origin. At the
same time, point-of-care companion diagnostics are becoming available that
will make personalized treatment a reality. This is the so called ‘precision
medicine’. Practicing precision medicine requires the overcoming of a
number of key hurdles, both scientific and nonscientific.
Results
In the last two years we focused on the AIRC 5x1000 project ‘Targeting
resistances to EGFR directed therapies in colorectal cancer’ and designed
and conducted our first precision trial aimed at treating HER2 amplified
metastatic colorectal (mCRC) patients. Researchers from the Institute
recently demonstrated that HER2 amplification drives primary resistance to
EGFR directed treatment mCRC patients, and that HER2-amplified tumours
in mCRC patient-derived xenografts (xenopatients) showed tumour shrinkage
when treated with lapatinib and trastuzumab in combination. We therefore
designed HERACLES, a therapeutic trial of targeted therapy without
chemotherapy, to establish the efficacy of lapatinib and trastuzumab in HER2
amplified mCRC patients. Preliminary results in the clinical trial suggest that
only specific amplification profiles drive responses in pluri-chemotherapy
and cetuximab resistant mCRC patients.
Projects and goals
We will continue to design ‘molecular-driven’ proofs of concept trials in
markers–enriched subpopulations suggested by the in-vitro and in vivo
results in the traslational programs of the Institute. Through several multiinstitutionals longitudinal studies we are building a storehouse of molecularly
and clinically annotated tumors samples that will allow researchers to mine
for new targets or ways to improve existing drugs, and clinician to select
patients to be ‘funneled’ into target-therapy treatments tailored to their
tumor molecular landscape. PROFILING, the prototype of these studies now
includes around 700 cases.
Team
Antonella Balsamo, Cosimo Martino, Marilì Vitiello
36 | Investigational Clinical Oncology
The CTU goal is to make precision
medicine possible in the Institute,
by shaping the clinical validation
path of new putative targets found
in the Institute preclinical programs. The CTU will accomplish
this goal by designing and conducting proof-of-concept (POC) trials
in marker-enriched populations,
triaged with the aid of molecular
markers companion studies.
Selected references
Bergmann L, et al. Actual
developments in European regulatory
and health technology assessment
of new cancer drugs: what does this
mean for oncology in Europe?
Ann Oncol. 2014, 25:303-6.
Garassino MC, et al. TAILOR trialists.
Erlotinib versus docetaxel as
second-line treatment of patients
with advanced non-small-cell lung
cancer and wild-type EGFR tumours
(TAILOR): a randomised controlled
trial. Lancet Oncol. 2013, 14:981-8.
De Marinis F, et al. A phase II study
of the histone deacetylase inhibitor
panobinostat (LBH589) in pretreated
patients with small-cell lung cancer. J
Thorac Oncol. 2013, 8:1091-4
HERLAP:
Personalizing HER2-positive breast cancer treatment.
To optimize HER2 molecular target
therapies to avoid, if possible,
standard cytotoxic chemotherapy
in this subgroup of patients with
breast cancer.
Selected references
Montemurro F, Scaltriti M: Biomarkers
of drugs targeting HER-family
receptors. J Pathol. 2014, 232:219229
Montemurro F, et al.Potential markers
of long-term benefit from single-agent
trastuzumab or lapatinib in HER2positive metastatic breast cancer.
Molecular Oncology. 2014, 8:20-26
Montemurro F, Di Cosimo S, Arpino
G: Human epidermal growth factor
receptor 2 (HER2)-positive and
hormone-receptor positive breast
cancer: new insights into molecular
interactions and clinical implications.
Ann Oncol. 2013, 24:2715-2724
Montemurro F, et al. Hormone
receptor expression and activity of
trastuzumab with chemotherapy in
HER2-positive advanced breast cancer
patients. Cancer 2012, 118:17-26
Filippo Montemurro MD
Unit of Breast Cancer
[email protected]
Rationale
The HER2 oncogene is amplified in 15% of breast cancer, a phenomenon
that is associated with overexpression of its product, the HER tyrosine
kinase receptor. The combination of drugs targeting HER2 with conventional
chemotherapy has proven successful in improving the prognosis of women
whose breast cancer carries this abnormality. Newer HER2 targeting
treatments are more and more effective, but often associated with increased
complexity and costs. The identification of biomarker of optimal response to
HER2-targeting agents would allow, in selected cases, simplified treatments
and the omission of conventional chemotherapy without compromising
efficacy.
Results
HER2-positive breast cancer patients whose tumors co-express high levels of
the estrogen receptor (ER) may be less sensitive to the monoclonal antibody
trastuzumab combined with chemotherapy. A subset of HER2-positive breast
cancer patients could be spared cytotoxic chemotherapy.
HER2-positive cancers of women achieving long-lasting benefits from antiHER2 treatments without chemotherapy in the randomized phase II HERLAP
trial, shared common molecular features. This allowed the identification of
candidate biomarkers of particular sensitivity to anti–HER2 therapy.
Projects and goals
(i) To confirm the candidate biomarkers identified in the HERLAP study in
the ongoing HERLAP2 study, a phase II, prospective, multi-Institutional trial
where women will receive two anti-HER2 agents, trastuzumab and lapatinib,
in combination as upfront treatment for HER2-positive metastatic breast
cancer; (ii) to establish pre-clinical model to study mechanisms of resistance
or susceptibility to anti HER2-treatments related to the candidate biomarkers
that have been identified in the HERLAP and HERLAP2 clinical trials; (iii)
to establish patient-derived xenograft (Xenopatients) of HER2-positive/
ER-positive and HER2-positive/ER-negative tumors to study strategies to
circumvent resistance to molecularly targeted therapies.
Team
Sonia Capellero, Caterina Aversa, Elena Geuna, Rossella Martinello
Investigational Clinical Oncology | 37
AGNOSTOS:
Target Therapy and Cancer of unknown primary (CUP).
Valentina Rossi MD
Center for Metastasis of
Unknown Primary Cancers (CUPs)
[email protected]
Rationale
Cancer of unknown primary (CUP) is defined as metastatic cancer in the
absence of a clinically detectable anatomically defined primary tumor site,
after an adequate diagnostic evaluation. This condition defines a highly
malignant syndrome which accounts for up to 6% of the whole cancer
population and - at the present - still lacking appropriate therapies. While
the majority of CUP related studies are focused on how best track down the
putative cancer of origin, the real enigma of this syndrome is related to its
biological and genetic setting as supported by growing evidence suggesting
that indeed the rationale for personalized targeted therapies is in the cancer
cells genomic alteration, rather than in the tissue of origin.
Results
Given the highly aggressive metastatic phenotype of CUPs we focused
on the Met oncogene, a key player of the ‘invasive growth program’, and
recently demonstrated a five-time higher mutational incidence (15% vs 3%
of unselected cancer population) in a cohort of about 50 CUP patients.
Projects and goals
The activity of the CUPs Center is part of AGNOSTOS, a larger program to
optimize the diagnosis and the treatment of CUP patients at our Institute.
AGNOSTOS includes a comprehensive diagnostic algorithm and a phase 2
trial in which patients, whose metastases harbor an ‘actionable’ molecular
alteration including MET, will be treated with the accordingly appropriate
targeted drug. Treatment outcome will be monitored with both traditional
methods and BEAMing, a ‘liquid biopsy’ technique that uses the putative
‘actionable’ target as a marker of therapeutic success. In addition, as part
of this program, the tumor material of CUPs, which harbor specific genetic
lesions, will be implanted in immune-compromised mice to establish humanmouse (Xenopatients) models of CUPs for preclinical studies.
Team
Giulia Maria Stella, Tiziana Venesio, Claudio Valizia, Patrizia Morbini
38 | Investigational Clinical Oncology
The project aims to build a genomic profile of CUPs, focusing
on MET and selected oncogenes
known to be frequently mutated in
cancer.
Selected references
Stella GM, et al. MET mutations in
cancers of unknown primary origin
(CUPs).
Hum Mutat. 2011, 32:44-50
Stella GM, Luisetti M, Pozzi E,
Comoglio PM. Oncogenes in nonsmall-cell lung cancer: emerging
connections and novel therapeutic
dynamics.
Lancet Respir Med. 2013, 1:251-61.
Stella GM, Benvenuti S, Comoglio PM.
Targeting the MET oncogene in cancer
and metastases.
Expert Opin Investig Drugs. 2010,
19:1381-94
Research Topic 4: Applied Clinical Research
The the ultimate task of the Institute is the development of clinical research integrated with health assistance,
also through nationally- and internationally-controlled clinical trials. With the introduction of molecular therapies,
it has been understud that a specific disease can have different characteristics that need different therapies.
Treatments are therefore oriented toward personalized therapy, which needs a very sophisticated molecular
diagnostics armamentarium that the Institute is able to provide. Ongoing clinical research integrates the Divisions,
the Laboratories and the Facilities, in order to allow the synergy among different highly-specialized technologies
and complementary, diagnostic and therapeutic know-how. The research goal is the progress of science, but the
figure and the well-being of the patient are an absolute priority. The participation in the experimental protocols
is voluntary and is suggested to patients according to the biological and clinical characteristics of the disease.
The Ethics Committee of IRCCS-FPO guarantees that patients receive only treatments having solid scientific
bases and that they are monitored with the most serious attention. In compliance with the Declaration of
Helsinki, the patient who does not wish to participate in a trial receives the best “standard” therapy.
Oncologists, surgeons, radiologists and radiotherapists cooperate with researchers to design clinical trials
based on molecular data, intended to verify and generate hypotheses. In order to make this cooperation
productive, the Institute manages a daily net of interactions involving formal aspects (seminars and meetings),
training (refresher courses and lessons) and operational efforts (contacts with the pharmaceutical companies,
regulatory and management instruments).
Clinical Research is the last and more important haven to improve the assistance to cancer patients, to
increase their life expectancy and to provide them with the most appropriate, safe and effective therapeutic
approach according to the genetic characteristics of their own tumor. The controlled clinical Protocol is the final
product of the overall work of a multidisciplinary group composed of basic researchers, oncologists, surgeons,
pathologists, pharmacologists, radiologists and nuclear medicine doctors, biostatistics and bioinformatics
scientists, research healthcare assistants, data managers and legal experts. Below the main projects of the
Applied Clinical Research are listed, followed by the table of Controlled Clinical Trials.
Research Topic 4 concerns:
4.1. Pathology of colorectal cancer onset and progression
4.2. Development of new therapeutic strategies
4.3. New approaches to surgical oncology
4.4. Laboratory Medicine, Imaging and Radiotherapy
Applied Clinical Research | 39
Stochastic modelling of colorectal tumorigenesis.
Mauro Risio MD
Unit of Pathology
[email protected]
Rationale
Knowledge of the biological machineries sustaining the progression rates
and times of Colorectal Adenomas will be crucial to refine the natural history
assumptions in Colorectal Cancer (CRC) screening modeling. The rate for
evolution is driven by genetic events that promote tumor progression: in
the large majority of cases of sporadic CRC, genetic instability occurs at
chromosomal level (CIN) and gain in the long arm of chromosome 20 is one
of the most frequent chromosomal aberration observed in CRC. Narrowing
down the gain region, several studies aiming to identify candidate genes
for tumor progression on 20q have pinpointed Aurora Kinase A (AURKA),
a member of cell-cycle regulating serine-threonine kinases family and an
important regulatory protein of the mitotic process. An association between
aberrant expression of AURKA and chromosomal instability has been
assumed because accurate regulation of mitotic spindle formation is crucial
for proper chromosome segregation.
Results
Morphological features of dysplasia have been demonstrated to be
inadequate when used in colorectal cancer screening programmes. It has
been proven that a unique histologic feature, tumour budding is a reliable
marker of the metastatic potential of cancerised adenomas and an overall
fair level of diagnostic agreement has been demonstrated in T1 CRCr when
using quantitative and selective methods for its measurement.
Projects and goals
The research aims to unravel genetic and histological markers of evolving CRC
precursors: (i) To explore the role of multipolar mitoses and of “catastrophic
mitoses” (caspase2-mediated intramitotic apoptosis) as histological
markers of progression; (ii) to assess the involvement of AURKA gene in
the various steps of CRC evolution; (iii) to evaluate the profile of expression
of key molecules, (HIF-1alpha, VEGF, GLUT1, CA IX, CA XII), in cancerised
colorectal adenomas.
Team
Ivana Sarotto, Laura Casorzo, Carmine Dell’Aglio, Elena Frangipane,
Alessandra Santarelli
40 | Applied Clinical Research
Identification of molecular and
morphological markers of premalignant colon tumor lesions, to rationalize diagnostic and therapeutic
strategies.
Selected references
Risio M, et al. Virtual microscopy for
histology quality assurance of screendetected polyps. J Clin Pathol. 2010,
63: 916-20
Vieth M, Quirke P, Lambert R, von
Karsa L, Risio M. Annex to Quirke
et al QA in pathology in colorectal
cancer screening and diagnosis:
annotations in colorectal lesions.
Virchows Arch. 2011, 458 :21-30
Puppa G, et al. Diagnostic
reproducibility of tumor budding
in colorectal cancer: a multicentre,
multinational study using virtual
microscopy. Histopathology. 2012,
61:562-575
Venesio T, et al. M. Oxidative DNA
damage drives carcinogenesis in
MUTYH-associated-polyposis by
specific mutations of mitochondrial
and MAPK genes.Mod Pathol. 2013,
26:1371-81
Identification of potential targets in cancer of the biliary tract
Development of new cancer therapies to improve the prognosis of
biliary carcinomas, a group highly
lethal malignancy.
Selected references
Leone F, et al. Panitumumab
in combination with infusional
oxaliplatin and oral capecitabine for
conversion therapy in patients with
colon cancer and advanced liver
metastases. The MetaPan study.
Cancer. 2013, 119:3429-35.
Marino D, et al. Biliary tract
carcinomas: from chemotherapy
to targeted therapy. Crit Rev Oncol
Hematol. 2013, 85:136-48.
Pignochino Y, et al. Targeting EGFR/
HER2 pathways enhances the
antiproliferative effect of gemcitabine
in biliary tract and gallbladder
carcinomas. BMC Cancer. 2010,
10:631.
Francesco Leone MD
Unit for the Study of Tumors of the
Gastrointestinal Tract
[email protected]
Rationale
Biliary tract carcinoma has generally poor prognosis. Treatment options
are weak and the expectation of long-term survival is extremely limited. A
better understanding of the pathogenetic mechanisms could identify novel
therapeutic strategies.
Results
We have identified, some potential molecular targets including SRC and
EGFR. On the basis of these observations, we have designed and coordinated
a multicenter clinical trial designed to explore the activity of a combination
of chemotherapy (gemcitabine + oxaliplatin) with the monoclonal antibody
panitumumab in patients with unresectable biliary carcinoma and KRAS
wild-type status. The primary objective of the study is to demonstrate that
the combination of chemotherapy and EGFR antibodies it gets a disease
control superior to chemotherapy alone.
Projects and goals
Identify new potential therapeutic targets for cancer of the biliary tract in
preclinical studies and develop, based on the results obtained, innovative
clinical trials.
Team
Federica Colombi, Renato Ferraris, Donatella Arino, Caterina Peraldo Neia
Applied Clinical Research | 41
Cell therapy for metastatic tumors
Fabrizio Carnevale-Schianca MD
Unit of Cell Therapy
[email protected]
Rationale
Despite important progresses reached by conventional treatments (e.g.
chemotherapy, radiotherapy), and the recent enthusiasms brought by
molecular targeted therapies, many types of metastatic tumors remain
incurable. Cell therapy is still considered a promising approach, with potential
positive synergism with recent molecular targeted therapies. The potential of
cell therapy has been demonstrated by hematopoietic cell transplant (HCT) in
hematologic malignancies, by new immunomodulatory agents (Ipilimumab;
anti-PD1) against some solid tumors and by adoptive immunotherapy using
ex-vivo expanded anti-tumor T lymphocytes.
Results
Among others, we demonstrated that HCT may be considered an ideal
platform to support further antitumor immunologic interventions. Results
were produced within single and multi-center trials in the settings of Multiple
Myeloma, Colorectal Cancer and other solid tumors.
Projects and goals
(i) investigation and modulation of immunologic mechanisms underlying
the GVT and GVHD events, (ii) definition and clinical application of adoptive
immunotherapies against metastatic tumors. The program includes: (a)
preclinical and clinical evaluation of the immunomodulatory potential of
Cyclofosfamide in the post HCT setting. (b) Evaluation of the immunereconstitution. (c) Induction of T lymphocytes against tumor associated
antigens, and (d) generation and adoptive infusion of Cytokine-induced killer
cells against mesenchymal tumors and melanoma.
Team
Dario Sangiolo, Daniela Caravelli, Valentina Coha, Susanna Gallo, Loretta
Gammaitoni, Lidia Giraudo, Valeria Leuci, Giulia Mesiano, Maja Todorovich
42 | Applied Clinical Research
Application of new cell-therapy
based strategies, to synergize with
molecular targeted therapies.
Selected references
Gammaitoni L, et al. Effective
Activity of Cytokine Induced Killer
Cells against Autologous Metastatic
Melanoma including Cells with
Stemness Features.
Clin Cancer Res. 2013, 19:4347-58
Todorovic M, et al. Ex Vivo Allogeneic
Stimulation Significantly Improves
Expansion of Cytokine-Induced
Killer Cells Without Increasing Their
Alloreactivity Across HLA Barriers.
J Immunother. 2012,35:579-586
Leuci V, et al.Transient proteasome
inhibition as a strategy to
enhance lentiviral transduction of
hematopoietic CD34(+) cells and T
lymphocytes: implications for the
use of low viral doses and large-size
vectors.
J Biotechnol. 2011, 156:218-26.
Integrated therapies for the treatment of sarcomas
To explore, autonomously or in
cooperative trials, new therapeutic
hypotheses.
Selected references
Sangiolo D, et al., Cytokine-induced
killer cells eradicate bone and softtissue sarcomas. Cancer Res 2014,
74:119-29
Pignochino Y, et al., The Combination
of Sorafenib and Everolimus
Abrogates mTORC1 and mTORC2
upregulation in osteosarcoma
preclinical models. Clin Cancer Res
2013, 19:2117-31
Stacchiotti S, et al. Phase II study of
imatinib in advanced chordoma. J
Clin Oncol 2012, 30:914-20
Grignani G, et al. A phase II
trial of sorafenib in relapsed
and unresectable high-grade
osteosarcoma after failure of
standard multimodal therapy: an
Italian Sarcoma Group study. Ann
Oncol 2012, 23:508-16
Giovanni Grignani MD
Unit for Investigation and Therapy of Sarcomas
[email protected]
Rationale
According to genetic alterations, we now identify sarcomas so called genetically
simple (i.e.: diseases characterized by a genetic alteration clearly related to
the tumor pathogenesis) and complex (i.e.: tumors carrying multiple genetic
defects none of which is clearly pathogenetic or pathognomic). Within
this scenario, translational research has been focused on the discovery of
molecular mechanisms endowed with potential therapeutic implications.
Results
(i) We have joined international clinical trials on new chemotherapeutic drugs
(Trabectedin, TH-302, Palifosfamide, Eribulin) to explore the possibility to
overcome the well-known sarcoma refractoriness; (ii) we have identified the
role of ERK1 and 2 in osteosarcoma and coordinated a phase II trial on the
activity of the multikinase inhibitor ‘Sorafenib’ in the treatment of relapsed
and unresectable disease; (iii) we have completed a phase II study showing
the activity of ‘imatinib’ in advanced chordoma after failure of standard
therapies; (iv) we have shown the efficacy of ‘Pazopanib’ in advanced soft
tissue sarcomas after failure of standard therapies.
Projects and goals
(i) From preclinical data showing that mTOR pathway is activated during
Sorafenib treatment of relapsed osteosarcoma, we are running a phase II
study in relapsed and unresectable osteosarcoma, exploring the combination
of ‘Sorafenib with Everolimus’; (ii) we are involved in a prospective phase
II clinical study on the monoclonal antibody ‘MorAb’ in refractory soft
tissue sarcomas; (iii) we are developing a preclinical model of adoptive
immunotherapy to integrate both target and chemotherapy.
Team
Ymera Pignochino, Lorenzo D’Ambrosio, Danilo Galizia, Federica Capozzi,
Paola Boccone, Sara Miano, Erica Palesandro, Annamaria Nuzzo
Reduction of osteosarcoma metastases in lungs after
sorafenib treatment (clinical trial OSTEO-BAY)
Applied Clinical Research | 43
Biomarkers in the systemic treatment of epithelial ovarian cancers.
Giorgio Valabrega MD
Unit for Gynecological Cancers
[email protected]
Rationale
Although multimodal treatments improved clinical outcome of ovarian cancer,
the cure rate has not changed significantly. After surgery, approximately 70%
of patients benefit from first-line chemotherapy (platinum compounds),
the others being intrinsically refractory. In addition, approximately 70% of
patients develop a secondary resistance. Therefore, a critical problem is the
management of primary and acquired resistance to platinum-based drugs.
There are promising targeted therapies (eg PARP inhibitors, MEK inhibitors,
inhibitors of VEGFRs), that must be adapted to the specific genetic and
epigenetic landscape of each ovarian cancer.
Results
Collection, in progress, of vital tumor material from patients with ovarian
cancer surgery. Part of this material is systematically implanted into
immunocompromised mice (Xenopatients) to establish in vivo models for
preclinical studies.
Projects and goals
Establishment of human-mouse models (Xenopatients) of platinum
refractory/resistant ovarian carcinomas, to identify biomarkers of sensitivity
/resistance to standard chemotherapy and targeted therapies.
Team
Giuliana Cavalloni
44 | Applied Clinical Research
Development of new therapeutic
strategies
Selected references
Montemurro F, Prat A, Rossi V,
Valabrega G, Sperinde J, PeraldoNeia C, Donadio M, Galván P, Sapino
A, Aglietta M, Baselga J, Scaltriti
M. Potential biomarkers of longterm benefit from single-agent
trastuzumab or lapatinib in HER2positive metastatic breast cancer. Mol
Oncol. 2014 8(1):20-6
Geuna E, Montemurro F, Aglietta M,
Valabrega G. Potential of afatinib in
the treatment of patients with HER2positive breast cancer. Breast Cancer
(Dove Med Press). 2012 4:131-7
Valabrega G, et al. HER2-positive
breast cancer cells resistant to
trastuzumab and lapatinib lose
reliance upon HER2 and are sensitive
to the multitargeted kinase inhibitor
sorafenib. Breast Cancer Res Treat.
2011, 130(1):29-40.
Cancer Pain.
Applied research with clinical
value.
Selected references
Anselmetti GC, et al. Percutaneous
vertebroplasty in osteoporotic
patients: an institutional experience
of 1,634 patients with long-term
follow-up. J Vasc Interv Radiol. 2011,
22:1714-20
Moselli NM, Baricocchi E, Ribero D,
Sottile A, Suita L, Debernardi F.
Intraoperative epidural analgesia
prevents the early proinflammatory
response to surgical trauma. Results
from a prospective randomized
clinical trial of intraoperative epidural
versus general analgesia. Ann Surg
Oncol. 2011, 18:2722-31.
Moselli NM, Cruto M, Massucco P,
Savojardo M, Debernardi F. Long-term
continuous subcutaneous infusion of
ketoprofen combined with morphine:
a safe and effective approach to
cancer pain. Clin J Pain. 2010,
26:267-74.
Felicino Debernardi MD
Unit of Anesthesia and Pain Management
[email protected]
Rationale
Pain management is a mandatory action in cancer palliation.
Results
Continuous subcutaneous infusion of ketoprofen combined with morphine is a
safe method for treating cancer pain. A study evaluating the impact of epidural
anesthesia versus general anesthesia on perioperative immunological status
in patients with colon cancer demonstrated that postoperative complications
are higher in the second group.
Projects and goals
(i) Development of an pain management educational program direct to
physicians and paramedics; (ii) survey on incidence and pain management
in medical and surgical units and in outpatients services; (iii) compilation of
guidelines and protocols for pain control.
Team
Massimo Battistella
Applied Clinical Research | 45
Irreversible electroporation as treatment
of pancreatic adenocarcinoma.
Michele De Simone MD
Unit of Surgical Oncology
[email protected]
Rationale
80% of pancreactic cancer patients are not manageable by surgery, because
of metastatic disease (40%) or local major vessels involvement (40%). In
recent years, many loco-regional therapies have been studied and most of
them elicit tumor cell ablation by mean of thermal injury (Thermoablation).
However these procedures are not free for side effects. Irreversible
Electroporation (IRE) can lead to a selective neoplastic tissue destruction
sparing normal tissues. IRE is based on short and low-voltage electric pulses
that causes nanopores in the double layer of phospholipids in the cellular
membrane.
Results
Preclinical studies on animal models showed that IRE doesn’t damage
structures of hepatic hilum, coeliac trunk and duodenum. Similarly human
studies have demonstrated that IRE is safe towards bile ducts, vessels,
urethra, spermatic ducts and neurovascular structures. Moreover ongoing
clinical trials in not resectable locally advanced pancreatic adenocarcinomas
are endwed with promising results.
Projects and goals
(i) Evaluating feasibility and safety of IRE, in organs other than pancreas
(liver); (ii) evaluating overall survival and recurrence rate after IRE for not
resectable advanced pancreatic adenocarcinoma; (iii) Evaluating capacity of
IRE in downsizing/downstaging in not resectable pancreatic neoplasia and
rate of patients becoming suitable for surgery.
Team
Armando Cinquegrana, Andrea Muratore, Alfredo Mellano, Marco Vaira
46 | Applied Clinical Research
Elaboration of a new techniques for
treatment of pancreatic and liver
cancer.
Selected references
Cavaliere F, et al.Prognostic factors
and oncologic outcome in 146
patients with colorectal peritoneal
carcinomatosis treated with
cytoreductive surgery combined
with hyperthermic intraperitoneal
chemotherapy: Italian multicenter
study S.I.T.I.L.O.Eur J Surg Oncol.
2011, 37:148-54.
Baratti D, et al.Multicystic peritoneal
mesothelioma: outcomes and
patho-biological features in a
multi-institutional series treated
by cytoreductive surgery and
Hyperthermic Intraperitoneal
Chemotherapy (HIPEC).Eur J Surg
Oncol. 2010 ,36:1047-53.
Vaira M, et al.Treatment of peritoneal
carcinomatosis from colonic cancer
by cytoreduction, peritonectomy
and hyperthermic intraperitoneal
chemotherapy (HIPEC). Experience
of ten years.In Vivo. 2010, 24:79-84.
New strategies for breast cancer local-regional control
Re-definition of local-regional breast cancer treatment according to
the risk of relapse
Selected references
Ponzone R, Baum M. Loco-regional
therapy and breast cancer survival:
searching for a link. Breast. 2013,
22:510-4.
Montemurro F, et al. Omission of
axillary dissection after a positive
sentinel node dissection may
influence adjuvant chemotherapy
indications in operable breast cancer
patients. Ann Surg Oncol. 2012,
19:3755-61.
D’Alonzo M, et al. Clinical and
radiological predictors of nippleareola complex involvement in breast
cancer patients. Eur J Cancer. 2012,
48:2311-8.
Rivolin A, et al. Nipple-areola complex
sparing mastectomy with periareolar
pexy for breast cancer patients
with moderately ptotic breasts. J
Plast Reconstr Aesthet Surg. 2012,
65:296-303
Riccardo Ponzone MD
Unit of Gynecological Oncology
[email protected]
Rationale
The prevention and early detection of local-regional relapses requires
a better understanding of the complex relationship between the primary
tumor and its metastatic dissemination. One of the main objectives of breast
cancer treatment is the introduction of more effective ways to integrate the
advancements in imaging, surgery and radiotherapy.
Results
(i) Treatment of the primary tumor: we experimented magnetic resonance
imaging for the pre-operative staging of breast cancer, accelerated partial
breast radiotherapy and new techniques for mastectomy with preservation
of the whole skin envelope; (ii) treatment of regional lymph nodes: we
tested several algorithms to predict the involvement of non-sentinel lymphnodes, the effect of omitting axillary dissection on the indication to adjuvant
therapies and the technique of “axillary reverse mapping” to spare the
lymphatic channels of the arm.
Projects and goals
(i) Development of new strategies for selecting patients at increased risk
of local-regional recurrence; (ii) Validation of the safety of new surgical
approaches; (iii) Implementation of platforms of “pre-surgical therapy” for
assessing innovative drugs.
Team
Franziska Kubatzki, Furio Maggiorotto, Alessandra Magistris, Francesco
Marocco, Stefania Renditore, Alessandro Rivolin, Paola Sgandurra,
Salvatore Carlucci.
Applied Clinical Research | 47
Identification of new markers of thromboembolic events
Antonino Sottile MD
Laboratory Medicine
[email protected]
Rationale
Recent studies showed that apheresis procedures worsen the prothrombotic
state of patients, even leading to the chance that, during the reinfusion of
the cells, thrombotic events could happen. In particular, it is essential to have
new analytes, more sensitive and specific, suitable for early diagnosis and
patients monitoring.
Results
The laboratory is engaged in the identification of new markers of neoplastic
pathology by using the most innovative measurement techniques with
cutting-edge instrumentation. We use a new tests for the determination of
fecal occult blood, to identify the early metabolic alterations provoked by
colon cancer.
Projects and goals
For cancer patients, venous thromboembolism (VTE) is the most frequent
and the second cause of death. The prothrombotic state is worsened by
chemotherapy, surgery, central venous catheter insertion (CVC) and,
more in general, by invasive therapies to which the patients are often
subjected. A percentage of patients between 0.3% and 28.3% show venous
thromboembolism clinically, while a percentage of patients between 27%
and 66% show it after x-ray examination. Our project aims ad identifying
new laboratory tests allowing the selections of patients who may have more
chances to develop venous thrommboembolism.
Team
Monica Mangioni, Alessandra Polo, Sara Saponaro
48 | Applied Clinical Research
To improve laboratory tests for
early warning of venous thromboembolism.
Selected references
Robella M, et al. Treatment
of peritoneal carcinomatosis
from ovarian cancer by surgical
cytoreduction and hyperthermic
intraperitoneal chemotherapy
(HIPEC).
Minerva Chir. 2014, 69:27-35.
Robella M, et al. Treatment of diffuse
malignant peritoneal mesothelioma
(DMPM) by cytoreductive surgery and
HIPEC. Minerva Chir.2014, 69:9-15.
Sottile A, et al. A pilot study
evaluating serum pro-prostatespecific antigen in patients with rising
PSA following radical prostatectomy.
Oncol Lett. 2012, 3:819-824
Applications of Computer Assisted Diagnosis (CAD) in Radiology
The diagnostic imaging, improved
by CAD systems, allows to anticipate tumor diagnosis at an early
asymptomatic phase. In the future,
the integration of radiological and
biological data will detect tumor
with indolent clinical course and
promote a better individual
treatment planning.
Selected references
Porpiglia F,et al. The roles of
multiparametric MRI, PCA3, and PHI:
which is the best predictor of prostate
cancer after a negative biopsy?
Results of a prospective study. J Urol.
2014, pii:S0022-5347:00052-4.
Iussich G, et al. CT colonography:
preliminary assessment of a doubleread paradigm that uses computeraided detection as the first reader.
Radiology. 2013, 268:743-51.
Regge D, et al. Efficacy of
computer-aided detection as a
second reader for 6-9-mm lesions
at CT colonography: multicenter
prospective trial. Radiology. 2013,
266:168-76.
Daniele Regge MD
Image and Data Processing Laboratory (IDP)
[email protected]
Rationale
The more variables are provided by Computed Tomography (CT) and
Magnetic Resonance Imaging (MRI), the more time-consuming it is even for
the experienced reader to integrate all the available information into one
reliable final report. To deal with these complex problems CAD systems have
been introduced to provide a list of disease suspicious areas as final output.
The CAD systems automatically highlight suspicious regions on a parametric
color-coded map representing the cancer probability on a voxel-wise basis.
Results
The IDP Lab developed CAD systems for the 1) early diagnosis of Colorectal
Cancer on CT-colonography (CTC); 2) diagnosis of breast cancer on MR
images; 3) diagnosis of prostate cancer on multiparametric MR exams with
endorectal coil. The perfomances of the CTC-CAD have been assessed on a
large cohort of asymptomatic individuals.
Projects and goals
The IDP Lab is completing the development of a CAD system for prostate
cancer detection. Future efforts will be focused on the reduction of false
positive prompts, through the refinement of mathematical algorithms, and
the implementation of a CAD system aimed to provide a reliable estimate
of prostate tumour aggressiveness, especially in those cases characterized
by indolent clinical course. Imaging data will be integrated with molecular
information, using statistical classification methods.
Team
Gabriella Iussich, Ilaria Bertotto, Delia Campanella, Gabriele Chiara,
Veronica Deantoni, Maria Rosaria Di Virgilio, Valentina Giannini, Antonio
Manca, Laura Martincich, Anna Vignati, Simone Mazzetti
Visualization of a polyp of the colon by acquisition with virtual colonoscopy.
Applied Clinical Research | 49
“Personalized” Radiation-therapy based on genetic,
biological, and “theragnostic” parameters
Pietro Gabriele MD
Unit of Radiotherapy
[email protected]
Adapting radiotherapy treatment to
the modern concept of “personalized medicine” (“Precision radiotherapy”).
Rationale
Aim of the project is to define a model to optimize the use of radiotherapy
using genomics information and “theragnostic” data, in order to personalize
the treatment. The IMRT techniques (Intensity Modulated Radiation Therapy),
SBRT (Stereo Body Radiotherapy) and IGRT (Image Guided Radiotherapy)
give us the opportunity to use high doses, perfectly “sculpted” on the basis
of the areas that are going to be treated. A further improvement of the
treatment is provided by the “daily image control”.
Gatti M, et al. Accelerated partial
breast irradiation using 3D conformal
radiotherapy: toxicity and cosmetic
outcome. Breast. 2013, 22:1136-41.
Results
(i) We’ve proved –in collaboration with the radiobiology laboratory - that
ionizing radiation lead to the expression of an oncogene (Met) responsible
for invasivity and metastasis control. This was a contribution to the ‘vexata
questio’ about the possible radiotherapy side effects on metastatic spread;
(ii) we implemented the “large fields” technology using Tomotherapy
and the protocol for IMRT-IGRT treatment of the head and neck cancer;
Zucca S, Carau B, Solla I, Garibaldi E,
Farace P, Lay G, Meleddu G, Gabriele
P. Prostate image-guided radiotherapy
by megavolt cone-beam CT.
Strahlenther Onkol. 2011, 187:473-8.
Projects and goals
(i) To evaluate the possibile impact of the information about genetics and
molecular biology of the Glioblastoma Multiforme (GBM) on the treatment
plan with ionizing radiation; (ii) to personalize the radiotherapy treatment
(Adaptive Radiotherapy) of a variety of tumors (including pancreas,spine,
pleura and gynecological tumors); (iii) to implement, as cohordinators,
a multicentric prospective trial on IMRT-IGRT radiotherapy linked to
biomolecular markers (European Project “Computational Horizons in
Cancer”: CHIC).
Team
Gaetano Belli, Gabriella Cattari, Marco Gatti, Gabriele Petrilli, Antonia
Salatino, Antonella Suma, Domenico Gabriele
50 | Applied Clinical Research
Selected references
Valdagni R, et al. Increasing the risk
of late rectal bleeding after high-dose
radiotherapy for prostate cancer: the
case of previous abdominal surgery.
Results from a prospective trial.
Radiother Oncol. 2012, 103:252-5.
Gabriele P, et al. Radio hyperthermia
for re-treatment of superficial
tumours. Int J Hyperthermia. 2009,
25:189-98.
Personalized medicine driven by
nuclear molecular imaging in cancer patients
Providing personalized molecular imaging strategies in cancer
patients.
Selected references
Laura Evangelista, Stefania Redana,
Manuela Racca, Elena Geuna, Lorenzo
Vinante, Giulia Zago, Valentina De
Carolis, Cristina Ghiotto, Giorgio
Saladini, Teresio Varetto. FDG Avidity
at PET/CT During Adjuvant Hormonal
Therapy in Patients With Breast
Cancer. Clinical nuclear medicine.
2014, 39:e135-41.
Teresio Varetto, Durval C Costa
The new UEMS-EACCME criteria for
accreditation of live educational
events (LEEs): another step forward
to improve the quality of continuing
medical education (CME) in Europe.
European Journal of Nuclear
Medicine. 2014, 41:191-6.
Teresio Varetto, Durval C.Costa
Continuing Medical Education
Committee and UEMS-EACCME.
European Journal of Nuclear
Medicine. 2013, 40:470-4
Teresio Varetto MD
Unit of Nuclear Medicine
[email protected]
Rationale
Molecular imaging with nuclear medicine techniques and particularly with
Positron Emission Tomography (PET) is a rapidly evolving field of imaging
science by which molecular events are non-invasively visualized, characterized
and measured in living cells, animals and humans. With PET imaging it is
now possible to non-invasively evaluate various important cancer features in
clinical patients, such as metabolism, cellular proliferation, tumor hypoxia,
tumor angiogenesis and receptor expression. In some cases, it is also
possible to assess the expression of receptor proteins on the cell surface.
Results
We demonstrated in preclinical models, that it is possible to assess –by PET
imaging- the expression of genes involved in tumor development, growth and
invasion (oncogenes). In particular we developed a technology based on the
use of monoclonal antibodies labeled with Indium and Zirconium radioactive
isotopes.
Projects and goals
Our future goals will be to develop PET and SPECT “molecular imaging”
techniques with radiolabeled monoclonal antibodies targeting proteins
encoded by oncogenes. And to assess their value in predicting response to
therapy and in targeting resistance to the new molecular therapies.
Team
Manuela Racca, Paola Scapoli, Valeria Pirro
Applied Clinical Research | 51
“Safe” dose escalation with Tomotherapy
Michele Stasi PhD
Unit of Medical Physics
[email protected]
Rationale
The use of sophisticated imaging tools (MRI, PET/CT) and new radiotherapy
techniques, such as Image Guided Radiation Therapy (IGRT) Intensity
Modulated Radiation Therapy (IMRT) and Tomotherapy will achieve better
conformal radiation dose with respect to 3D standard conformal radiotherapy.
Results
(i) Tumor masses segmentation is achieved by using three point dynamic PET
combined to anomalies detector, adaptive threshold and/or by exploiting
multi-parametric MRI images; (ii) Pre-treatment dosimetry is assessed by
patient-specific dosimetry for volumetric IMRT plans.
Projects and goals
“Safe” dose escalation for prostate, rectum, head & neck, mesothelioma,
pancreas, sarcoma, breast and rare tumors in order to improve local tumor
control.
Team
Christian Bracco, Sara Bresciani, Claudia Cutaia, Amalia Didia, Angelo
Maggio, Anna Miranti, Matteo Poli
52 | Applied Clinical Research
Applied research with clinical
value.
Selected references
Bresciani S, et al. Tomotherapy
treatment plan quality assurance: the
impact of applied criteria on
passing rate in gamma index method.
Med Phys. 2013, 40:121711
Fellin G, et al. Long term
rectal function after high-dose
prostatecancer radiotherapy: Results
from a prospective cohort study.
Radiother Oncol. 2014, 110:272-7
Bresciani S, et al. Dose to organs at
risk in the upper abdomen in patients
treated with extended fields by
helical tomotherapy: a dosimetric
and clinical preliminary study. Radiat
Oncol. 2013, 8:247.
Gatti M, et al. Accelerated partial
breast irradiation using 3D conformal
radiotherapy: toxicity and cosmetic
outcome. Breast. 2013, 22:1136-41.
Personalized therapies in Medical Oncology
Personalized treatments to reduce
the risk of uneffective therapies
Selected references
Leone F, et al. Panitumumab in
combination with infusional
oxaliplatin and oral capecitabine for
conversion therapy in patients with
colon cancer and advanced liver
metastases. The MetaPan study.
Cancer. 2013, 119:3429-35
Montemurro F, et al. Current
status and future perspectives
in the endocrine treatment of
postmenopausal, hormone receptorpositive metastatic breast cancer.
Expert Opin Pharmacother. 2012,
13:2143-56.
Marino D, et al. Biliary tract
carcinomas: from chemotherapy
to targeted therapy. Crit Rev Oncol
Hematol. 2013, 85:136-48.
Massimo Aglietta MD
Medical Oncology
[email protected]
Rationale
The possibility of identifying molecular alterations potentially involved in
tumor progression is the mainstay of personalized antitumor therapy. In
epithelial and mesenchimal neoplasias, through molecular analysis of fresh
tumor sample or by studying ex vivo models (including xenopatients) we have
been able to formulate hypothesis and build prospective clinical trials to test
them.
Results
In epithelial neoplasias we have been looking for gene alterations predictive
of response to anti EGF therapies. (i) In mammary carcinoma during the
HERLAP study (see also 3.2) we have been collecting tumor samples of
patients treated with different anti HER-2 therapies. A gene profiling predictive
of an increased sensitivity to anti HER-2 treatment has been identified. Since
resistance invariably develops, further analyses are in progress to identify
molecular changes occurring at this stage. (ii) In preclinical models of
biliary tract cancer we have identified EGFR as a potential therapeutic
target in patients with K-ras WT tumors. A multicenter randomized phase
II study has been (VECTIBIL see also 4.2.1) conducted. (iii) Osteosarcoma
is a mesenchimal neoplasia with several molecular alterations potentially
involved in the neoplastic progression. In preclinical models we have provided
evidence of a pivotal role of MAP-K activations in tumor growth. On these
bases we have performed a phase II study in metastatic patients resistant
to chemotherapy to test the activity of Sorafenib, a multitarget inhibitor of
the MAP-K pathway. We have demonstrated a significant antitumor activity.
However secondary resistance associated to activation of m-TOR pathway
develops. Thus we we are performing a second phase II study (SERIO, see
also 4.2.3) to test if the m-TOR inhibitor Everolimus enhances the activity of
Sorafenib. Accrual is completed.
Projects and goals
Extensive molecular analysis of tumor tissue derived from clinical studies to
try to understand the mechanism beyond primary and secondary resistance
to target therapies.
Team
Paola Boccone, Antonio Capaldi, Marco Fizzotti, Lucia Garetto, Luisa Angela
Gioeni, Cinzia Ortega, Veronica Prati, Delia Rota Scalabrini, Fiorella Ruatta,
Celeste Cagnazzo, Cristina Realmuto
Applied Clinical Research | 53
54 | Clinical Services
Clinical Services
Piero Fenu MD
Direzione Sanitaria
[email protected]
The head of the department of clinical services participates in the strategic planning process and contributes,
with the formulation of proposals and opinions, to the hospital management. He directs health services and
is responsible for hygiene and prevention (hospital infection control and environmental hygiene). The clinical
service office monitors the appropriateness of admissions, the hospital stay lenghts, the average weight of the
so called ‘case mix’ and supervise the waiting list. He coordinates with the Operation Department the proper
use of spaces and the timely flow of goods and services.
The clinical service office:
(i) he is in charge of the control of the fulfillement of results obtained within the assigned objectives; (ii)
coordinates the facilities of the hospital including the provision of appropriate protocols; (iii) defines strategies
and guidelines for the extraordinary and/or urgent intervention; (iv) advices on building planning about further
hospital expansion; (v) Supervises the ‘conventional’ agreements and the related reports with the University
Clinical Services | 55
56 | Grant Office and Research Administration
Grant Office and Research Administration
Daniela Gramaglia PhD
[email protected]
Michelina Bruno Ms
[email protected]
The Scientific Director’ Office supervises, coordinates and manages the basic, translational and clinical scientific
research in the Institute. To this end, the Grant Office provides the scientific support for institute research
activities and acts as a liaison between researchers and funding agencies.
The Grant Office assists researchers in identifying appropriate research funding opportunities, centralizing all
information on major national and international, private or public, agencies, foundations, and institutions that
support research.
Whenever a call for a research grant is issued, it is advertised throughout the Institute by e-mail. The Grant
Office provides assistance to researchers in the preparation of applications, in the drawing up of the budget together with the administrative office of the Institute -, in completing the application forms and interpreting
the regulations of the granting agencies, assuring compliance with the sponsors’ policies and requirements.
In case of successful outcome of the proposals, the Grant Office helps in preparing reports, consortium
agreements with collaborating institutions, and renewal forms.
Grant Office and Research Administration | 57
CORE FACILITIES
Entering into new scientific challenges and aiming for breakthroughs require adapted technologies and a
research strategy. Candiolo Cancer Institute therefore pays extra attention to developing and attracting advanced
technologies in order to allow researchers to perform cutting-edge science in cancer research.
The Oncogenomics Center (OGC)
Genetic alterations in tumors are predictors of response or resistance to targeted therapies, and their identification
is mandatory for molecular diagnosis and therapeutic decisions. Technological advances in experimental and
informatics methodologies over the past 10 years have made possible the characterization of cancer genomes.
OGC is the supportive infrastructure for all genomic studies, including transcriptional, mutational and gene copy
number analyses of cells, tissues and liquid biopsies. Dedicated personnel and instrumentation are devoted to
provide services for qRT-PCR studies, Sanger and Next Generation Sequencing experiments, Gene Expression
Array analyses and BEAMing tests.
The Bioinformatics Center (BIC)
Modern research in cancer biology implies the collection of extensive data from experimental models concerning
specific genetic lesions that drive cancer initiation and progression. Such data will include, for example, large
sets of expression transcript profiling, comparative genomic hybridization profiling, whole genome sequencing,
immunohistochemical data, and morphologic data that will be peculiar to each specific tumor. Thus, a
bioinformatics platform for integrated data tracking and normalization is critical to the successful realization
of this endeavor.
BIC comprises a web-based bioinformatics platform (Laboratory Assistant Suite, LAS; http://devircc.polito.it/
wordpress/)that assists biomedical researchers in multiple activities, which range from tracking data generation
and execution of standard operating procedures (SOPs) to management of multidimensional molecular profiles
and complex data analysis and integration, by managing multiple independent databases that are linked
together in an interconnected network (‘oncogrid’).
The Oncology Imaging Center (OIC)
Basic research in disciptopics such as cell biology, molecular genetics and developmental biology has
provided invaluable insights into the regulatory circuits that govern cancer onset and progression. Within this
context, we postulate that imaging studies in cell topics and tissues will parallel genomic analyses and in vivo
experimentation, constituting an integrative platform for rapid testing of emerging research directions.
OIC technologies include comprehensive microscopic imaging systems, such as confocal microscopes, live-cell
devices for real-time monitoring of cellular behaviors, and high-throughput platforms for functional screens.
58 | Core Facilities
The Flow Cytometry Center (FLOCC)
Increasing evidence shows that tumors are structured in a hierarchical form, with a majority of cells undergoing
aberrant differentiation but retaining a proliferative capacity limited over time, and a tiny fraction of cancer
stem cells (CSCs) or cancer-initiating cells (CICs) that are able to self-renew and continuously regenerate or add
to the tumor.
FLOCC enables researchers to take advantage of state-of-the-art FACS (fluorescence-activated cell sorter)
technologies and dedicated personnel with highly specialized technical skills in order to tackle these issues, by
allowing analysis and prospective isolation of individual cancer cells within highly heterogeneous populations.
series of human cancer specimens directly transplanted into mice (“xenopatients”).
XEBB provides researchers with a collection of more than 400 liver metastases from colorectal cancer that have
been systematically transplanted in immunocompromised mice to obtain more than 200 stable tumor topics
(xenopatients), which are available for any kind of in vivo/ex vivo study.
The Xenopatients’ Biobank (XEBB)
Immortalized cancer cells exhibit a genetic drift, a biological compliance and phenotypic features different from
original cancers in patients. Another drawback of such an approach is that the catalogue of currently available
cell topics is inevitably finite, and possibly poor for some tumour types. Therefore, experiments with cell topics
cannot recapitulate the wide heterogeneity of human malignancy that occurs among individuals on a population
basis. One way to tackle this issue is to perform population-based in vivo studies by using large
Pharmacodynamics and Pharmacokinetics Service
The Pharmacodynamics and Pharmacokinetics Service is an autonomous facility within the Insitute of Candiolo
devoted to the study of neoplastic diseases in preclinical models. The most significant activitiy of the Service is
the “xenopatients” project, which provides for the molecular classification of the surgical samples taken from
the patients and their propagation in vivo in immunocompromised mice. The Institute of Candiolo employs
animal testing but, thanks to the deep feeling that moves the Institution and its researchers, it adjoins solid
ethical behaviours. The goal is to improve the procedures prescribed by the current national and international
regulations, through an Ethical Committee for Animal Experimentation.
Team
Piero Alberto, Paola Bernabei, Jadwiga Biela, Michela Buscarino, Daniela Cantarella, Dario Caponi, Giorgio
Corti, Alessandro Fiori, Emanuele Geda, Stefania Giove, Alberto Grand, Barbara Martinoglio, Laura Palmas,
Roberta Porporato, Natalia Santoro, Solange Tienga, Donatella Valdembri, Carlo Zanon
Core Facilities | 59
60 | List of Pubblications
List of Pubblications | 61
List of Publications 2013
Laboratory of Cancer Cell Biology
Cagnoni G, Tamagnone L.
Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression.
Oncogene:Epub ahead of print,2013, I.F. 7.357
Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA,
Tamagnone L, Mazzone M.
Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits
Angiogenesis and Restores Antitumor Immunity.
Cancer Cell:24:695-709,2013, I.F. 24.755
Tamagnone L, Rehman M.
To Die or Not to Die: Sema3E Rules the Game.
Cancer Cell:24:564-6,2013, I.F. 24.755
Laboratory of Cell Adhesion Dynamics
Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A, Valdembri D, Serini G, Michieli P.
Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET.
Clinical Cancer Research:19:2381-92,2013, I.F. 7.837
Cerruti B, Puliafito A, Shewan AM, Yu W, Combes AN, Little MH, Chianale F, Primo L, Serini G, Mostov KE, Celani
A, Gamba A.
Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures.
The Journal of Cell Biology:203:359-72,2013, I.F. 10.822
Laboratory of Transgenic Mouse Models
Gu C, Giraudo E.
The role of semaphorins and their receptors in vascular development and cancer.
Experimental Cell Research:319:1306-16,2013, I.F. 3.557
Laboratory of Neuorovascular Biology
Graziano S, Marchiò S, Bussolino F, Arese M.
A peptide from the extracellular region of the synaptic protein a Neurexin stimulates angiogenesis and the
vascular specific tyrosine kinase Tie2.
Biochemical and Biophysical Research Communications:432:574-9,2013, I.F. 2.406
Laboratory of Vascular Oncology
Bo S, Celani A.
Entropic anomaly and maximal efficiency of microscopic heat engines
Physical Review. E, Statistical, nonlinear, and Soft Matter Physics:87:50102,2013, I.F. 2.313
Cardaci S, Soster M, Bussolino F, Marchiò S.
The V1/V2 loop of HIV-1 gp120 is necessary for Tat binding and consequent modulation of virus entry.
FEBS Letters:587:2943-51,2013, I.F. 3.582
Frascella F, Ricciardi S, Rivolo P, Moi V, Giorgis F, Descrovi E, Michelotti F, Munzert P, Danz N, Napione L, Alvaro
M, Bussolino F.
A fluorescent one-dimensional photonic crystal for label-free biosensing based on BLOCH surface waves.
Sensors:13:2011-22,2013, I.F. 1.953
62 | List of Pubblications
Graziano S, Marchiò S, Bussolino F, Arese M.
A peptide from the extracellular region of the synaptic protein a Neurexin stimulates angiogenesis and the
vascular specific tyrosine kinase Tie2.
Biochemical and Biophysical Research Communications:432:574-9,2013, I.F. 2.406
Loi M, Di Paolo D, Soster M, Brignole C, Bartolini A, Emionite L, Sun J, Becherini P, Curnis F, Petretto A, Sani M,
Gori A, Milanese M, Gambini C, Longhi R, Cilli M, Allen TM, Bussolino F, Arap W, Pasqualini R, Corti A, Ponzoni
M, Marchiò S, Pastorino F.
Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in
preclinical settings.
Journal of Controlled Release:170:233-41,2013, I.F. 7.633
Marchiò S, Astanina E, Bussolino F.
Emerging lymphae for the fountain of life.
The EMBO Journal:32:609-11,2013, I.F. 9.822
Petrelli A, Perra A, Cora D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM,
Giordano S, Columbano A.
MiRNA/gene profiling unveils early molecular changes and NRF2 activation in a rat model recapitulating human
HCC.
Hepatology:59:228-41,2013, I.F. 12.033
Pregno G, Frola E, Graziano S, Patrizi A, Bussolino F, Arese M, Sassoè-Pognetto M.
Differential regulation of neurexin at glutamatergic and GABAergic synapses.
Frontiers in Cellular Neuroscience:7:35,2013, I.F. 4.469
Seano G, Chiaverina G, Gagliardi PA, Di Blasio L, Sessa R, Bussolino F, Primo L.
Modeling human tumor angiogenesis in a three-dimensional culture system.
Blood:121:e129-37,2013, I.F. 9.060
Laboratory of Cell Migration
Cerruti B, Puliafito A, Shewan AM, Yu W, Combes AN, Little MH, Chianale F, Primo L, Serini G, Mostov KE, Celani
A, Gamba A.
Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures.
The Journal of Cell Biology:203:359-72,2013, I.F. 10.822
Seano G, Chiaverina G, Gagliardi PA, Di Blasio L, Sessa R, Bussolino F, Primo L.
Modeling human tumor angiogenesis in a three-dimensional culture system.
Blood:121:e129-37,2013, I.F. 9.060
Laboratory of Cancer Microenvironment
Arap W, Pasqualini R, Montalti M, Petrizza L, Prodi L, Rampazzo E, Zaccheroni N, Marchiò S.
Luminescent silica nanoparticles for cancer diagnosis.
Current Medicinal Chemistry:20:2195-211,2013, I.F. 4.070
Cardaci S, Soster M, Bussolino F, Marchiò S.
The V1/V2 loop of HIV-1 gp120 is necessary for Tat binding and consequent modulation of virus entry.
FEBS Letters:587:2943-51,2013, I.F. 3.582
Graziano S, Marchiò S, Bussolino F, Arese M.
A peptide from the extracellular region of the synaptic protein a Neurexin stimulates angiogenesis and the
vascular specific tyrosine kinase Tie2.
Biochemical and Biophysical Research Communications:432:574-9,2013, I.F. 2.406
List of Pubblications | 63
Loi M, Di Paolo D, Soster M, Brignole C, Bartolini A, Emionite L, Sun J, Becherini P, Curnis F, Petretto A, Sani M,
Gori A, Milanese M, Gambini C, Longhi R, Cilli M, Allen TM, Bussolino F, Arap W, Pasqualini R, Corti A, Ponzoni
M, Marchiò S, Pastorino F.
Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in
preclinical settings.
Journal of Controlled Release:170:233-41,2013, I.F. 7.633
Marchiò S, Astanina E, Bussolino F.
Emerging lymphae for the fountain of life.
The EMBO Journal:32:609-11,2013, I.F. 9.822
Pignochino Y, Dell’Aglio C, Basiricò M, Capozzi F, Soster M, Marchiò S, Bruno S, Gammaitoni L, Sangiolo D,
Torchiaro E, D’Ambrosio L, Fagioli F, Stefano Ferrari S, Alberghini M, Picci P, Aglietta M, Grignani G.
The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma
preclinical models.
Clinical Cancer Research:19:2117-31,2013, I.F. 7.837
Laboratory of Cancer Metabolism
Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A, Valdembri D, Serini G, Michieli P.
Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET.
Clinical Cancer Research:19:2381-92,2013, I.F. 7.837
Michieli P, Di Nicolantonio F.
Targeted therapies: Tivantinib--a cytotoxic drug in MET inhibitor’s clothes?
Nature Reviews. Clinical Oncology:10:372-4,2013, I.F. 15.031
Vigna E, Pacchiana G, Chiriaco C, Cignetto S, Fontani L, Michieli P, Comoglio PM.
Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor.
Journal of Molecular Medicine:92:65-76,2013, I.F. 4.768
Laboratory of Exploratory Research
Bardelli A, Corso S., Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A,
Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A,
Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio PM, Trusolino L, Di Nicolantonio F, Giordano S,
Siena S.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Cancer Discovery:3:658-73,2013, I.F. 10.143
Benvenuti S, Gentile A, Lazzari L, Arnesano A, Trusolino L, Comoglio PM.
An’in-cell trial’ to assess the efficacy of a monovalent anti-MET antibody as monotherapy and in association
with standard cytotoxics.
Molecular Oncology:pii: S1574-7891(13)00178-6. doi: 10.1016/j.molonc.2013.12.006,2013, I.F. 6.701
Boccaccio C, Comoglio PM.
The MET oncogene in glioblastoma stem cells: implications as a diagnostic marker and a therapeutic target.
Cancer Research:73:3193-9,2013, I.F. 8.650
Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Leonce S, Ferry G, Da Violante G, Bouzom F, Cattan V,
Jacquet-Bescond A, Comoglio PM, Lockhart BP, Boutin JA, Cordi A, Ortuno JC, Pierre A, Hickman JA, Cruzalegui
FH, Depil S.
S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in
Association with Bevacizumab.
Molecular Cancer Therapeutics:12:1749-62,2013, I.F. 5.599
64 | List of Pubblications
Stella GM, Luisetti M, Pozzi E, Comoglio PM.
Oncogenes in non-small-cell lung cancer: emerging connections and noveltherapeutic dynamics.
The Lancet. Respiratory Medicine:1:251-61,2013, I.F. Nuova Rivista
Vigna E, Pacchiana G, Chiriaco C, Cignetto S, Fontani L, Michieli P, Comoglio PM.
Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor.
Journal of Molecular Medicine:92:65-76,2013, I.F. 4.768
Laboratory of Cancer Genetics
Lorenzato A, Biolatti M, Delogu G, Capobianco G, Farace C, Dessole S, Cossu A, Tanda F, Madeddu R, Olivero
M, Di Renzo MF.
AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian
cancer cells.
Experimental Cell Research:319:2627-36,2013, I.F. 3.557
Maniscalco L, Millán Y, Iussich S, Denina M, Sánchez-Céspedes R, Gattino F, Biolatti B, Sasaki N, Nakagawa T,
Di Renzo MF, de Las Mulas JM, De Maria R
Activation of mammalian target of rapamycin (mTOR) in triple negative feline mammary carcinomas.
BMC Veterinary Research:9:doi: 10.1186/1746-6148-9-80.,2013, I.F. 1.861
Pavan S, Musiani D, Torchiaro E, Migliardi G, Gai M, Cunto FD, Erriquez J, Di Renzo MF.
HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor.
International Journal of Cancer:134:1289-99,2013, I.F. 6.198
Laboratory of Precision Medicine
Bardelli A, Corso S., Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A,
Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A,
Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio PM, Trusolino L, Di Nicolantonio F, Giordano S,
Siena S.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Cancer Discovery:3:658-73,2013, I.F. 10.143
Benvenuti S, Gentile A, Lazzari L, Arnesano A, Trusolino L, Comoglio PM.
An’in-cell trial’ to assess the efficacy of a monovalent anti-MET antibody as monotherapy and in association
with standard cytotoxics.
Molecular Oncology::pii: S1574-7891(13)00178-6. doi: 10.1016/j.molonc.2013.12.006,2013, I.F. 6.701
Bertotti A, Trusolino L.
From Bench to Bedside: Does Preclinical Practice in Translational Oncology Need Some Rebuilding?
Journal of the National Cancer Institute:105:1426-27,2013, I.F. 14.336
Gelsomino F, Facchinetti F, Haspinger ER, Garassino MC, Trusolino L, De Braud F, Tiseo M.
Targeting the MET gene for the treatment of non-small-cell lung cancer.
Critical Reviews in Oncology/Hematology:89:284-99,2013, I.F. 4.637
Isella C, Mellano A, Galimi F, Petti C, Capussotti L, De Simone M, Bertotti A, Medico E, Muratore A.
MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases.
Annals of Surgery:257:1089-95,2013, I.F. 6.329
Pavan S, Musiani D, Torchiaro E, Migliardi G, Gai M, Cunto FD, Erriquez J, Di Renzo MF.
HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor.
International Journal of Cancer:134:1289-99,2013, I.F. 6.198
List of Pubblications | 65
Sangiolo D, Mesiano G, Gammaitoni L, Leuci V, Todorovic M, Giraudo L, Cammarata C, Dell’Aglio C, D’Ambrosio
L, Pisacane A, Sarotto I, Miano S, Ferrero I, Carnevale-Schianca F, Pignochino Y, Sassi F, Bertotti A, Piacibello
W, Fagioli F, Aglietta M, Grignani G.
Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.
Cancer Research:74:119-29,2013, I.F. 8.650
Laboratory of Oncogenomics
Annaratone L, Medico E, Rangel N, Castellano I, Marchiò C, Sapino A, Bussolati G.
Search for Neuro-Endocrine Markers (Chromogranin A, Synaptophysin and VGF) in Breast Cancers. An integrated
Approach Using Immunohistochemistry and Gene Expression Profiling.
Endocrine Pathology::Epub ahead of print,2013, I.F. 1.600
D’Amico L, Patanè S, Grange C, Bussolati B, Isella C, Fontani L, Godio L, Cilli M, D’Amelio P, Isaia G, Medico E,
Ferracini R, Roato I.
Primary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism
signature.
British Journal of Cancer:108:2525-36,2013, I.F. 5.082
Isella C, Mellano A, Galimi F, Petti C, Capussotti L, De Simone M, Bertotti A, Medico E, Muratore A.
MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases.
Annals of Surgery:257:1089-95,2013, I.F. 6.329
Pincini A, Tornillo G, Orso F, Sciortino M, Bisaro B, Leal Mdel P, Lembo A, Brizzi MF, Turco E, De Pittà C, Provero
P, Medico E, Defilippi P, Taverna D, Cabodi S.
Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells.
Cell Cycle:12:2409-22,2013, I.F. 3.521
Spaccarotella E, Pellegrino E, Ferracin M, Ferreri C, Cuccuru G, Liu C, Iqbal J, Cantarella D, Taulli R, Provero P,
Di Cunto F, Medico E, Negrini M, Chan WC,Inghirami G, Piva R.
STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive
anaplastic large cell lymphoma.
Haematologica:99:116-24,2014, I.F. 5.935
Voena C, Di Giacomo F, Panizza E, D’Amico L, Boccalatte FE, Pellegrino E, Todaro M, Recupero D, Tabbò F,
Ambrogio C, Martinengo C, Bonello L, Pulito R,Hamm J, Chiarle R, Cheng M, Ruggeri B, Medico E, Inghirami G.
The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1.
Oncogenesis:doi: 10.1038/oncsis.2013.7.,2013, I.F.
Zamperone A, Pietronave S, Merlin S, Colangelo D, Ranaldo G, Medico E, Di Scipio F, Berta GN,
Follenzi A, Prat M.
Isolation and characterization of a spontaneously immortalized multipotent mesenchymal cell line derived
from mouse subcutaneous adipose tissue.
Stem Cells and Development:22:2873-84,2013, I.F. 4.670
Zecchin D, Boscaro V, Medico E, Barault L, Martini M, Arena S, Cancelliere C, Bartolini A, Crowley EH, Bardelli
A, Gallicchio M, Di Nicolantonio F.
BRAF V600E is a determinant of sensitivity to proteasome inhibitors.
Molecular Cancer Therapeutics:12:2950-61,2013, I.F. 5.599
66 | List of Pubblications
Laboratory of Pharmacogenomics
Bardelli A, Corso S., Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A,
Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A,
Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio PM, Trusolino L, Di Nicolantonio F, Giordano S,
Siena S.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Cancer Discovery:3:658-73,2013, I.F. 10.143
Crowley EH, Di Nicolantonio F, Loupakis F, Bardelli A.
Liquid biopsy: monitoring cancer-genetics in the blood.
Nature Reviews. Clinical Oncology:10:472-84,2013, I.F. 15.031
Crowley EH, Arena S, Lamba S, Di Nicolantonio F, Bardelli A.
Targeted Knock-in of the Polymorphism rs61764370 Does Not Affect KRAS Expression but Reduces let-7 Levels.
Human Mutation:35:208-14,2013, I.F. 5.213
Di Nicolantonio F, Bardelli A.
Mouse models of Kras-mutant colorectal cancer: valuable GEMMs for drug testing?
Clinical Cancer Research:19:2794-6,2013, I.F. 7.837
Michieli P, Di Nicolantonio F.
Targeted therapies: Tivantinib--a cytotoxic drug in MET inhibitor’s clothes?
Nature Reviews. Clinical Oncology:10:372-4,2013, I.F. 15.031
Valtorta E, Misale S, Sartore-Bianchi A, Nagtegaal ID, Paraf F, Lauricella C, Dimartino V, Hobor S, Jacobs
B, Ercolani C, Lamba S, Scala E, Veronese S, Laurent-Puig P, Siena S, Tejpar S, Mottolese M, A Punt CJ,
Gambacorta M, Bardelli A, Di Nicolantonio F.
KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy.
International Journal of Cancer:133:1259-65,2013, I.F. 6.198
Zecchin D, Boscaro V, Medico E, Barault L, Martini M, Arena S, Cancelliere C, Bartolini A, Crowley EH, Bardelli
A, Gallicchio M, Di Nicolantonio F.
BRAF V600E is a determinant of sensitivity to proteasome inhibitors.
Molecular Cancer Therapeutics:12:2950-61,2013, I.F. 5.599
Zecchin D, Arena S, Martini M, Sassi F, Pisacane A, Di Nicolantonio F, Bardelli A.
Modeling tumor progression by the sequential introduction of genetic alterations into the genome of human
normal cells.
Human Mutation:34:330-7,2013, I.F. 5.213
Laboratory of Molecular Genetics
Bardelli A, Corso S., Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A,
Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A,
Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio PM, Trusolino L, Di Nicolantonio F, Giordano S,
Siena S.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Cancer Discovery:3:658-73,2013, I.F. 10.143
Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A, Valdembri D, Serini G, Michieli P.
Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET.
Clinical Cancer Research:19:2381-92,2013, I.F. 7.837
List of Pubblications | 67
Bottos A, Bardelli A.
Oncogenes and angiogenesis: a way to personalize anti-angiogenic therapy?
Cellular and Molecular Life Sciences:,2013, I.F. 5.615
Crowley EH, Di Nicolantonio F, Loupakis F, Bardelli A.
Liquid biopsy: monitoring cancer-genetics in the blood.
Nature Reviews. Clinical Oncology:10:472-84,2013, I.F. 15.031
Crowley EH, Arena S, Lamba S, Di Nicolantonio F, Bardelli A.
Targeted Knock-in of the Polymorphism rs61764370 Does Not Affect KRAS Expression but Reduces let-7 Levels.
Human Mutation:35:208-14,2013, I.F. 5.213
Di Nicolantonio F, Bardelli A.
Mouse models of Kras-mutant colorectal cancer: valuable GEMMs for drug testing?
Clinical Cancer Research:19:2794-6,2013, I.F. 7.837
Esposito A, Bardelli A, Criscitiello C, Colombo N, Gelao L, Fumagalli L, Minchella I, Locatelli M, Goldhirsch A,
Curigliano G.
Monitoring tumor-derived cell-free DNA in patients with solid tumors: Clinical perspectives and research
opportunities.
Cancer Treatment Reviews::Epub ahead of print,2013, I.F. 6.024
Martini M, Russo M, Lamba S, Vitiello E, Crowley EH, Sassi F, Romanelli D, Frattini M, Marchetti A, Bardelli A.
Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated
RAS signaling in driving tumorigenesis.
Cancer Research:73:1912-21,2013, I.F. 8.650
Valtorta E, Misale S, Sartore-Bianchi A, Nagtegaal ID, Paraf F, Lauricella C, Dimartino V, Hobor S, Jacobs
B, Ercolani C, Lamba S, Scala E, Veronese S, Laurent-Puig P, Siena S, Tejpar S, Mottolese M, A Punt CJ,
Gambacorta M, Bardelli A, Di Nicolantonio F.
KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy.
International Journal of Cancer:133:1259-65,2013, I.F. 6.198
Zecchin D, Boscaro V, Medico E, Barault L, Martini M, Arena S, Cancelliere C, Bartolini A, Crowley EH, Bardelli
A, Gallicchio M, Di Nicolantonio F.
BRAF V600E is a determinant of sensitivity to proteasome inhibitors.
Molecular Cancer Therapeutics:12:2950-61,2013, I.F. 5.599
Zecchin D, Arena S, Martini M, Sassi F, Pisacane A, Di Nicolantonio F, Bardelli A.
Modeling tumor progression by the sequential introduction of genetic alterations into the genome of human
normal cells.
Human Mutation:34:330-7,2013, I.F. 5.213
Laboratory of Gene Transfer
Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A, Valdembri D, Serini G, Michieli P.
Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET.
Clinical Cancer Research:19:2381-92,2013, I.F. 7.837
D’Amico L, Patanè S, Grange C, Bussolati B, Isella C, Fontani L, Godio L, Cilli M, D’Amelio P, Isaia G, Medico E,
Ferracini R, Roato I.
Primary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism
signature.
British Journal of Cancer:108:2525-36,2013, I.F. 5.082
68 | List of Pubblications
Olwill SA, Joffroy C, Gille H, Vigna E, Matschiner G, Allersdorfer A, Lunde BM, Jaworski J, Burrows JF, Chiriaco
C, Christian HJ, Hülsmeyer M, Trentmann S,Jensen K, Hohlbaum AM, Audoly L.
A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligandindependent activity.
Molecular Cancer Therapeutics:12:2459-71,2013, I.F. 5.599
Vigna E, Pacchiana G, Chiriaco C, Cignetto S, Fontani L, Michieli P, Comoglio PM.
Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor.
Journal of Molecular Medicine:92:65-76,2013, I.F. 4.768
Laboratory of Molecular Biology
Bardelli A, Corso S., Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A,
Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A,
Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio PM, Trusolino L, Di Nicolantonio F, Giordano S,
Siena S.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Cancer Discovery:3:658-73,2013, I.F. 10.143
Corso S, Giordano S
Cell-Autonomous and Non-Cell-Autonomous Mechanisms of HGF/MET-Driven Resistance to Targeted Therapies:
From Basic Research to a Clinical Perspective.
Cancer Discovery:3:978-92,2013, I.F. 10.143
Giordano S, Columbano A.
Met as a therapeutic target in HCC: facts and hopes.
Journal of Hepatology:60:442-52,2013, I.F. 9.858
Migliore C, Giordano S.
Resistance to targeted therapies: a role for microRNAs?
Trends in Molecular Medicine:19:633-42,2013, I.F. 9.571
Petrelli A, Perra A, Cora D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM,
Giordano S, Columbano A.
MiRNA/gene profiling unveils early molecular changes and NRF2 activation in a rat model recapitulating human
HCC.
Hepatology:59:228-41,2013, I.F. 12.033
Rapa I, Volante M, Migliore C, Farsetti A, Berruti A, Vittorio Scagliotti G, Giordano S, Papotti M.
Human ASH-1 Promotes Neuroendocrine Differentiation in Androgen Deprivation Conditions and Interferes With
Androgen Responsiveness in Prostate Cancer Cells.
Prostate:73:1241-9,2013, I.F. 3.843
Laboratory of Cancer Stem Cells Research
Boccaccio C, Comoglio PM.
The MET oncogene in glioblastoma stem cells: implications as a diagnostic marker and a therapeutic target.
Cancer Research:73:3193-9,2013, I.F. 8.650
Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, De Bacco F, Menietti E, Han M, Rideout WM 3rd,
Perera T, Bertotti A, Trusolino L, Comoglio PM, Boccaccio C.
MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.
Cancer Research. 74(6):1857-69,2013 I.F. 8.650
List of Pubblications | 69
Unit of Clinical Trials
Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti
L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A,
Marsoni S; TAILOR trialists.
Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and
wild-type EGFR tumours (TAILOR): a randomised controlled trial.
The Lancet Oncology:14:981-8,2013, I.F. 25.117
Unit of Breast Cancer
Anselmetti GC, Manca A., Marcia S, Chiara G, Marini S, Baroud G, Regge D, Montemurro F.
Vertebral Augmentation with Nitinol Endoprosthesis: Clinical Experience in 40 Patients with 1-Year Follow-up.
Cardiovascular and Interventional Radiology:37:193-202,2013, I.F. 2.138
Gatti M, Ponzone R, Bresciani S, Panaia R, Kubatzki F, Maggiorotto F, Di Virgilio MR, Salatino A, Baiotto B,
Montemurro F, Stasi M, Gabriele P.
Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and cosmetic outcome.
Breast:22:1136-41,2013, I.F. 1.967
Milani A, Sangiolo D, Montemurro F, Aglietta M, Valabrega G.
Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives.
Annals of Oncology:24:1740-8,2013, I.F. 7.384
Montemurro F, Aglietta M.
Duration of trastuzumab for HER2-positive breast cancer.
The Lancet Oncology:14:678-9,2013, I.F. 25.117
Montemurro F, Di Cosimo S, Arpino G.
Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new
insights into molecular interactions and clinical implications.
Annals of Oncology:24:2715-24,2013, I.F. 7.384
Montemurro F, Prat A, Rossi V, Valabrega G, Sperinde J, Peraldo-Neia C, Donadio M, Galván P, Sapino A, Aglietta
M, Baselga J, Scaltriti M.
Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic
breast cancer.
Molecular Oncology:8:20-6,2013, I.F. 6.701
Montemurro F, Scaltriti M.
Biomarkers of Drugs Targeting HER-family Signaling in Cancer.
The Journal of Pathology:232:219-29,2013, I.F. 7.585
Montemurro F.
Upfront adjuvant aromatase inhibitors in women with lobular breast cancer.
European Journal of Cancer:49:3376-7,2013, I.F. 5.061
Recupero D, Daniele L, Marchiò C, Molinaro L, Castellano I, Cassoni P, Righi A, Montemurro F, Sismondi P, Biglia
N, Viale G, Risio M, Sapino A.
Spontaneous and pronase-induced HER2 truncation increases the trastuzumab binding capacity of breast
cancer tissues and cell lines.
The Journal of Pathology:229:390-9,2013, I.F. 6.310
70 | List of Pubblications
Rossi V, Nolè F, Redana S, Adamoli L, Martinello R, Aurilio G, Verri E, Sapino A, Viale G,
Aglietta M, Montemurro F.
Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumabbased therapy.
Breast:23:44-9,2013, I.F. 1.967
Center for Metastasis of Unknown Primary Cancers (CUPs)
Rossi V, Nolè F, Redana S, Adamoli L, Martinello R, Aurilio G, Verri E, Sapino A, Viale G, Aglietta M,
Montemurro F.
Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumabbased therapy.
Breast:23:44-9,2013, I.F. 1.967
Unit of Pathology
De Leon MP, L’Urso ED, Pucciarelli S, Agostini M, Nitti D, Roncucci L, Benatti P, Pedroni M, Kaleci S, Balsamo
A, C Laudi C, Di Gregorio C, Viel A, Rossi G, Venesio T.
Clinical and molecular features of attenuated adenomatous polyposis in northern Italy
Techniques in Coloproctology:17:79-87,2013, I.F. 1.538
Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG,
Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta
M, Sangiolo D.
Effective Activity of Cytokine-Induced Killer Cells against Autologous Metastatic Melanoma Including Cells with
Stemness Features.
Clinical Cancer Research:19:4347-58,2013, I.F. 7.837
Recupero D, Daniele L, Marchiò C, Molinaro L, Castellano I, Cassoni P, Righi A, Montemurro F, Sismondi P, Biglia
N, Viale G, Risio M, Sapino A.
Spontaneous and pronase-induced HER2 truncation increases the trastuzumab binding capacity of breast
cancer tissues and cell lines.
The Journal of Pathology:229:390-9,2013, I.F. 6.310
Venesio T, Balsamo A, Errichiello E, Ranzani GN, Risio M.
Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of
mitochondrial and MAPK genes.
Modern Pathology:26:1371-81,2013, I.F. 5.253
Unit for the Study of Tumors of the Gastrointestinal Tract
Leone F, Artale S, Marino D, Cagnazzo C, Cascinu S, Pinto C, Fornarini G, Tampellini M, Di Fabio F, SartoreBianchi A, De Carlis L, Pugliese R, Capussotti L, Gioeni L, Siena S, Aglietta M.
Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients
with colon cancer and advanced liver metastases: The MetaPan study.
Cancer:119:3429-35,2013, I.F. 5.201
Unit of Cell Therapy
Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG,
Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta
M, Sangiolo D.
Effective Activity of Cytokine-Induced Killer Cells against Autologous Metastatic Melanoma Including Cells with
Stemness Features.
Clinical Cancer Research:19:4347-58,2013, I.F. 7.837
Leuci V, Mesiano G, Gammaitoni L, Aglietta M, Sangiolo D.
Genetically Redirected T Lymphocytes for Adoptive Immunotherapy of Solid Tumors.
Current Gene Therapy:Epub ahead of print,2013, I.F. 5.318
List of Pubblications | 71
Leuci V, Mesiano G, Gammaitoni L, Todorovic M, Giraudo L, Fabrizio CS, Aglietta M, Sangiolo D.
Ex Vivo-Activated MHC-Unrestricted Immune Effectors for Cancer Adoptive Immunotherapy.
Anti-Cancer Agents in Medicinal Chemistry:14:211-22,2013, I.F. 2.610
Milani A, Sangiolo D, Montemurro F, Aglietta M, Valabrega G.
Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives.
Annals of Oncology:24:1740-8,2013, I.F. 7.384
Sangiolo D, Mesiano G, Gammaitoni L, Leuci V, Todorovic M, Giraudo L, Cammarata C, Dell’Aglio C, D’Ambrosio
L, Pisacane A, Sarotto I, Miano S, Ferrero I, Carnevale-Schianca F, Pignochino Y, Sassi F, Bertotti A, Piacibello
W, Fagioli F, Aglietta M, Grignani G.
Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.
Cancer Research:74:119-29,2013, I.F. 8.650
Unit for Investigation and Therapy og Sarcomas
Galizia D, Palesandro E, Nuzzo AM, Pignochino Y, Aliberti S, Aglietta M, Grignani G.
Prolonged disease stability with trabectedin in a heavily pretreated elderly patient with metastatic leiomyosarcoma
of the thigh and renal failure: a case report and review of the literature.
Oncology Research:20:483-90,2013, I.F. 1.634
Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG,
Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta
M, Sangiolo D.
Effective Activity of Cytokine-Induced Killer Cells against Autologous Metastatic Melanoma Including Cells with
Stemness Features.
Clinical Cancer Research:19:4347-58,2013, I.F. 7.837
Pignochino Y, Dell’Aglio C, Basiricò M, Capozzi F, Soster M, Marchiò S, Bruno S, Gammaitoni L, Sangiolo D,
Torchiaro E, D’Ambrosio L, Fagioli F, Stefano Ferrari S, Alberghini M, Picci P, Aglietta M, Grignani G.
The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma
preclinical models.
Clinical Cancer Research:19:2117-31,2013, I.F. 7.837
Sangiolo D, Mesiano G, Gammaitoni L, Leuci V, Todorovic M, Giraudo L, Cammarata C, Dell’Aglio C, D’Ambrosio
L, Pisacane A, Sarotto I, Miano S, Ferrero I, Carnevale-Schianca F, Pignochino Y, Sassi F, Bertotti A, Piacibello
W, Fagioli F, Aglietta M, Grignani G.
Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.
Cancer Research:74:119-29,2013, I.F. 8.650
Unità per lo Studio dei Tumori dell’Apparato Ginecologico
Milani A, Sangiolo D, Montemurro F, Aglietta M, Valabrega G.
Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives.
Annals of Oncology:24:1740-8,2013, I.F. 7.384
Montemurro F, Prat A, Rossi V, Valabrega G, Sperinde J, Peraldo-Neia C, Donadio M, Galván P, Sapino A, Aglietta
M, Baselga J, Scaltriti M.
Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic
breast cancer.
Molecular Oncology:8:20-6,2013, I.F. 6.701
Unit of Surgical Oncology
Isella C, Mellano A, Galimi F, Petti C, Capussotti L, De Simone M, Bertotti A, Medico E, Muratore A.
MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases.
Annals of Surgery:257:1089-95,2013, I.F. 6.329
72 | List of Pubblications
Robella M, Vaira M, Marsanic P, Mellano A, Cinquegrana A, Sottile A, De Simone M.
Treatment of peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and HIPEC:
preliminary results in hi-ghly selected patients.
Minerva Chirurgica:68:551-8,2013, I.F. 0.328
Robella M, Vaira M, Marsanic P, Mellano A, Cinquegrana A, Sottile A, De Simone M.
Treatment of pseudomyxoma peritonei with cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy (HIPEC): a single center experience.
Minerva Chirurgica:68:569-77,2013, I.F. 0.328
Unit of Gynecological Oncology
Biglia N, Maggiorotto F, Liberale V, Bounous VE, Sgro LG, Pecchio S, D’Alonzo M, Ponzone R.
Clinical-pathologic features, long term-outcome and surgical treatment in a large series of patients with invasive
lobular carcinoma (ILC) and invasive ductal carcinoma (IDC).
European Journal of Surgical Oncology:39:455-60,2013, I.F. 2.614
Cimino D, De Pittà C, Orso F, Zampini M, Casara S, Penna E, Quaglino E, Forni M, Damasco C, Pinatel E, Ponzone
R, Romualdi C, Brisken C, De Bortoli M, Biglia N, Provero P, Lanfranchi G, Taverna D.
miR148b is a major coordinator of breast cancer progression in a relapse-associated microRNA signature by
targeting ITGA5, ROCK1, PIK3CA, NRAS, and CSF1.
The FASEB Journal:27:1223-35,2013, I.F. 5.704
Gatti M, Ponzone R, Bresciani S, Panaia R, Kubatzki F, Maggiorotto F, Di Virgilio MR, Salatino A, Baiotto B,
Montemurro F, Stasi M, Gabriele P.
Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and cosmetic outcome.
Breast:22:1136-41,2013, I.F. 1.967
Lunardi G, Piccioli P, Bruzzi P, Notaro R, Lastraioli S, Serra M, Marroni P, Bighin C, Mansutti M, Puglisi F,
Porpiglia M, Ponzone R, Bisagni G, Garrone O, Cavazzini G, Clavarezza M, Del Mastro L.
Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women
with early breast cancer treated with letrozole.
Breast Cancer Research and Treatment:137:167-74,2013, I.F. 4.469
Laboratory Medicine
Robella M, Vaira M, Marsanic P, Mellano A, Cinquegrana A, Sottile A, De Simone M.
Treatment of peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and HIPEC:
preliminary results in hi-ghly selected patients.
Minerva Chirurgica:68:551-8,2013, I.F. 0.328
Robella M, Vaira M, Marsanic P, Mellano A, Cinquegrana A, Sottile A, De Simone M.
Treatment of pseudomyxoma peritonei with cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy (HIPEC): a single center experience.
Minerva Chirurgica:68:569-77,2013, I.F. 0.328
Image and Data Processing Laboratory (IDP)
Anselmetti GC, Manca A., Marcia S, Chiara G, Marini S, Baroud G, Regge D, Montemurro F.
Vertebral Augmentation with Nitinol Endoprosthesis: Clinical Experience in 40 Patients with 1-Year Follow-up.
Cardiovascular and Interventional Radiology:37:193-202,2013, I.F. 2.138
Iafrate F, Iussich G, Correale L, Hassan C, Regge D, Neri E, Baldassari P, Ciolina M, Pichi A, Iannitti M, Diacinti
D, Laghi A.
Adverse events of computed tomography colonography: An Italian National Survey.
Digestive and Liver Disease:45:645-50,2013, I.F. 3.162
List of Pubblications | 73
Iussich G, Correale L, Senore C, Segnan N, Laghi A, Iafrate F, Campanella D, Neri E, Cerri F, Hassan C, Regge D.
CT Colonography: Preliminary Assessment of a Double-Read Paradigm That Uses Computer-aided Detection as
the First Reader.
Radiology:268:743-751,2013, I.F. 6.339
Macera A, Lario C, Petracchini M, Gallo T, Regge D, Floriani I, Ribero D, Capussotti L, Cirillo S.
Staging of colorectal liver metastases after preoperative chemotherapy. Diffusion-weighted imaging in
combination with Gd-EOB-DTPA MRI sequences increases sensitivity and diagnostic accuracy.
European Radiology:23:739-47,2013, I.F. 3.548
Neri E, Halligan S, Hellström M, Lefere P, Mang T, Regge D, Stoker J, Taylor S, Laghi A.
The second ESGAR consensus statement on CT colonography.
European Radiology:23:720-9,2013, I.F. 3.548
Regge D, Halligan S.
CAD: How it works, how to use it, performance.
European Journal of Radiology:82:1171-1176,2013, I.F. 2.512
Ribero D, Amisano M, Bertuzzo F, Langella S, Lo Tesoriere R, Ferrero A, Regge D, Capussotti L.
Measured Versus Estimated Total Liver Volume to Preoperatively Assess the Adequacy of the Future Liver
Remnant: Which Method Should We Use?
Annals of Surgery:258:801-6,2013, I.F. 6.329
Sali L, Grazzini G, Carozzi F, Castiglione G, Falchini M, Mallardi B, Mantellini P, Ventura L, Regge D, Zappa M,
Mascalchi M, Milani S.
Screening for colorectal cancer with FOBT, virtual colonoscopy and optical colonoscopy: study protocol for a
randomized controlled trial in the Florence district (SAVE study).
Trials:14:74,2013, I.F. 2.496
Unit of Radiotherapy
Gatti M, Ponzone R, Bresciani S, Panaia R, Kubatzki F, Maggiorotto F, Di Virgilio MR, Salatino A, Baiotto B,
Montemurro F, Stasi M, Gabriele P.
Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and cosmetic outcome.
Breast:22:1136-41,2013, I.F. 1.967
Maggio A, Carillo V, Cozzarini C, Perna L, Rancati T, Valdagni R, Gabriele P, Fiorino C.
Impact of the radiotherapy technique on the correlation between dose-volume histograms of the bladder wall
defined on MRI imaging and dose-volume/surface histograms in prostate cancer patients.
Physics in Medicine and Biology:58:N115-23,2013, I.F. 2.701
Munoz F, Guarneri A, Botticella A, Gabriele P, Moretto F, Panaia R, Ruggieri A, D’Urso L, Muto G, Filippi AR,
Ragona R, Ricardi U.
Salvage external beam radiotherapy for recurrent prostate adenocarcinoma after high-intensity focused
ultrasound as primary treatment.
Urologia Internationalis:90:288-93,2013, I.F. 1.065
Unit of Nuclear Medicine
Varetto T, Costa DC.
The new UEMS-EACCME criteria for accreditation of live educational events (LEEs): another step forward to
improve the quality of continuing medical education (CME) in Europe.
European Journal of Nuclear Medicine and Molecular Imaging:41:191-6,2013, I.F. 5.114
74 | List of Pubblications
Unit of Medical Physics
Bresciani S, Dia AD, Maggio A, Cutaia C, Miranti A, Infusino E, Stasi M.
Tomotherapy treatment plan quality assurance: The impact of applied criteria on passing rate in gamma index
method.
Medical Physics:40:121711. doi:10.1118/1.4829515,2013, I.F. 2.911
Fellin G, Rancati T, Fiorino C, Vavassori V, Antognoni P, Baccolini M, Bianchi C, Cagna E, Borca VC, Girelli G,
Iacopino B, Maliverni G, Mauro FA, Menegotti L, Monti AF, Romani F, Stasi M, Valdagni R.
Long term rectal function after high-dose prostatecancer radiotherapy: Results from a prospective cohort study.
Radiotherapy and Oncology:S0167-8140(13)00585-9. doi:10.1016/j.radonc.2013.09.028,2013, I.F. 4.520
Gatti M, Ponzone R, Bresciani S, Panaia R, Kubatzki F, Maggiorotto F, Di Virgilio MR, Salatino A, Baiotto B,
Montemurro F, Stasi M, Gabriele P.
Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and cosmetic outcome.
Breast:22:1136-41,2013, I.F. 1.967
Tabone M, Carbonatto P, Calvo A, Pellerito R, Stasi M, Daperno M, Rocca R.
Internal radiation by 131-iodine lipiodol in unresectable hepatocellular carcinoma.
Digestive and Liver Disease::doi: 10.1016/j.dld.2013.03.006,2013, I.F. 3.162
Medical Oncology
Amadori D, Aglietta M, Alessi B, Gianni L, Ibrahim T, Farina G, Gaion F, Bertoldo F, Santini D, Rondena R, Bogani
P, Ripamonti CI.
Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone
metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.
The Lancet Oncology:14:663-70,2013, I.F. 25.117
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M,
Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida
T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. (Aglietta M)
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and
sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
Lancet:381:295-302,2013, I.F. 39.060
Galizia D, Palesandro E, Nuzzo AM, Pignochino Y, Aliberti S, Aglietta M, Grignani G.
Prolonged disease stability with trabectedin in a heavily pretreated elderly patient with metastatic leiomyosarcoma
of the thigh and renal failure: a case report and review of the literature.
Oncology Research:20:483-90,2013, I.F. 1.634
Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG,
Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta
M, Sangiolo D.
Effective Activity of Cytokine-Induced Killer Cells against Autologous Metastatic Melanoma Including Cells with
Stemness Features.
Clinical Cancer Research:19:4347-58,2013, I.F. 7.837
Leone F, Artale S, Marino D, Cagnazzo C, Cascinu S, Pinto C, Fornarini G, Tampellini M, Di Fabio F, SartoreBianchi A, De Carlis L, Pugliese R, Capussotti L, Gioeni L, Siena S, Aglietta M.
Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients
with colon cancer and advanced liver metastases: The MetaPan study.
Cancer:119:3429-35,2013, I.F. 5.201
Leuci V, Mesiano G, Gammaitoni L, Aglietta M, Sangiolo D.
Genetically Redirected T Lymphocytes for Adoptive Immunotherapy of Solid Tumors.
Current Gene Therapy:Epub ahead of print,2013, I.F. 5.318
List of Pubblications | 75
Leuci V, Mesiano G, Gammaitoni L, Todorovic M, Giraudo L, Fabrizio CS, Aglietta M, Sangiolo D.
Ex Vivo-Activated MHC-Unrestricted Immune Effectors for Cancer Adoptive Immunotherapy.
Anti-Cancer Agents in Medicinal Chemistry:14:211-22,2013, I.F. 2.610
Martino M, Ballestrero A, Zambelli A, Secondino S, Aieta M, Bengala C, Liberati AM, Zamagni C, Musso M,
Aglietta M, Schiavo R, Castagna L, Rosti G, Bruno B, Pedrazzoli P.
Long-term survival in patients with metastatic breast cancer receiving intensified chemotherapy and stem cell
rescue: data from the Italian registry.
Bone Marrow Transplantation:48:414-8,2013, I.F. 3.541
Milani A, Sangiolo D, Montemurro F, Aglietta M, Valabrega G.
Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives.
Annals of Oncology:24:1740-8,2013, I.F. 7.384
Montemurro F, Aglietta M.
Duration of trastuzumab for HER2-positive breast cancer.
The Lancet Oncology:14:678-9,2013, I.F. 25.117
Montemurro F, Prat A, Rossi V, Valabrega G, Sperinde J, Peraldo-Neia C, Donadio M, Galván P, Sapino A, Aglietta
M, Baselga J, Scaltriti M.
Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic
breast cancer.
Molecular Oncology:8:20-6,2013, I.F. 6.701
Pignochino Y, Dell’Aglio C, Basiricò M, Capozzi F, Soster M, Marchiò S, Bruno S, Gammaitoni L, Sangiolo D,
Torchiaro E, D’Ambrosio L, Fagioli F, Stefano Ferrari S, Alberghini M, Picci P, Aglietta M, Grignani G.
The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma
preclinical models.
Clinical Cancer Research:19:2117-31,2013, I.F. 7.837
Ricardi U, Racca P, Franco P, Munoz F, Fanchini L, Rondi N, Dongiovanni V, Gabriele P, Cassoni P, Ciuffreda L,
Morino M, Filippi AR, Aglietta M, Bertetto O.
Prospective phase II trial of neoadjuvant chemo-radiotherapy with Oxaliplatin and Capecitabine in locally
advanced rectal cancer (XELOXART).
Medical Oncology:30:581,2013, I.F. 2.147
Rossi V, Nolè F, Redana S, Adamoli L, Martinello R, Aurilio G, Verri E, Sapino A, Viale G, Aglietta M, Montemurro
F.
Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumabbased therapy.
Breast:23:44-9,2013, I.F. 1.967
Sangiolo D, Mesiano G, Gammaitoni L, Leuci V, Todorovic M, Giraudo L, Cammarata C, Dell’Aglio C, D’Ambrosio
L, Pisacane A, Sarotto I, Miano S, Ferrero I, Carnevale-Schianca F, Pignochino Y, Sassi F, Bertotti A, Piacibello
W, Fagioli F, Aglietta M, Grignani G.
Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.
Cancer Research:74:119-29,2013, I.F. 8.650
Santini D, Procopio G, Porta C, Ibrahim T, Barni S, Mazzara C, Fontana A, Berruti A, Berardi R, Vincenzi B,
Ortega C, Ottaviani D, Carteni G, Lanzetta G, Virzì V, Santoni M, Silvestris N, Satolli MA, Collovà E, Russo A,
Badalamenti G, Fedeli SL, Tanca FM, Adamo V, Maiello E, Sabbatini R, Felici A, Cinieri S, ToniniG, Bracarda S.
Natural history of malignant bone disease in renal cancer: final results of an italian bone metastasis survey.
PLoS One:8:e83026.doi: 10.1371/journal.pone.0083026,2013, I.F. 3.730
76 | List of Pubblications